for a week or so, however, they appear to lose their tolerance to its effects. Interestingly, tolerance to different effects of the same drug can develop at varying rates. Heroin users, for example, become tolerant to the drug's euphoric effects more quickly than they do to its ability to interfere with breathing. Thus, because they tend to increase the amount of drug they take in order to attain the same high, heroin users risk death by asphyxiation.

To our knowledge no marijuana user has ever died of such an overdose. Nevertheless, there are likely to be patients for whom the development of tolerance to cannabinoids would outweigh the benefits of marijuana-based medicines. On the other hand, developing tolerance to certain effects of cannabinoids, such as short-term memory loss or inability to concentrate, could be seen as a benefit. Tolerance to the various cannabinoids may develop at different rates, so it will be important to evaluate their individual effects on mood, movement, memory, and attention if they are to be used as medicines.

People who use marijuana or who take oral THC (e.g., Marinol) appear to become tolerant to some of the drug's effects more quickly than to others. To document this phenomenon, researchers conducted a study of people who smoked marijuana on a daily basis. During the study period, one group of participants smoked marijuana cigarettes four times a day for four consecutive days, while the other group took THC pills on the same schedule. Both thought that the same amount of drug made them feel less and less “high” over the course of four days, but neither group thought that their drug-induced increases in appetite declined over that time. The marijuana-smoking group reported feeling “mellow” after smoking throughout the four days, while the THC-taking group never reported feeling “mellow.”16 The IOM team also heard from several people who had tried both smoked marijuana and oral THC to treat their medical symptoms and whose comparisons of the two drugs resembled those of the study participants.

In addition to human studies, scientists have conducted research on animals to study how tolerance to cannabinoids arises. Like the people in the clinical experiments described above, experimental animals that received THC on an ongoing basis ap-



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