VARIOUS theories have been put forward to elucidate the development of tolerance to a drug. For example, it has been observed by Zauder1 that “as tolerance develops (in the rat), the amount of morphine appearing in the urine decreases”. This was in accordance with Gross and Thomson's observations on the dog2. Cochin et al. 3, on the other hand, could not elucidate any significant differences in the pattern of excretion and, on their own admission, were at a loss to “account for the development of tolerance and physical dependence in the dog”, and suggested that “it becomes imperative to look to other explanations for the mechanisms of development of these phenomena”.