Possible Mechanism of Tolerance to Narcotic Drugs

While working on the metabolism of narcotic drugs, Axelrod observed that repeated administration of drugs produced tolerance to the drugs, but also reduced the body's ability to demethylate them enzymatically. In this article, he proposed a mechanism for tolerance to narcotic drugs. According to Axelrod, his hypothesis--that the continuous interaction of narcotic drugs with the demethylating enzymes deactivated the enzymes and possibly even the receptors of narcotic drugs, thus decreasing the subject's response to narcotic drugs--stimulated considerable criticism from some of his colleagues.