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TOLERANCE AND ADDICTION LIABILITY OF 6-DIMETHYLAMINO-4-4-DIPHENYLHEPTANONE-3 (METHADON)

HARRIS ISBELL, M.D.; ABRAHAM WIKLER, M.D.; NATHAN B. EDDY, M.D.; JOHN L. WILSON, M.D.; CLIFFORD F. MORAN, M.D.
JAMA. 1947;135(14):888-894. doi:10.1001/jama.1947.02890140008003.
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Because the pharmacologic properties of 6-dimethylamino-4-4-diphenyl-heptanone-3 ( methadon)1 resemble those of morphine and because methadon has been shown to be an effective analgesic substance in animals and in man,2 studies of the development of tolerance to certain actions of the drug and of its liability to cause addiction have been carried out by the United States Public Health Service. Since the drug may soon come into clinical use the purpose of the present report is to summarize briefly the data collected to date and to present an opinion of the liability of the drug to cause addiction. More detailed reports are to be published later.

I. ANIMAL EXPERIMENTS 

(a) Tolerance.—  Thermal stimulation being used,3 partial tolerance developed to the analgesic action in mice after administration of 5 mg. per kilogram subcutaneously once daily for twenty-nine days. In that period the degree of analgesic response was reduced nearly 50

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