Another important factor that determines the immediate effect of any drug is tolerance. Tolerance has two different connotations. The first, initial tolerance, is a measure of the amount of a drug which a subject must receive on first exposure to produce a designated degree of effect. A variety of innate and environmental factors contributes to initial tolerance among individuals. Different individuals require varying amounts of the drug to attain the same physical and mental effect.

The second connotation, which shall be referred to when we use the word tolerance, is that of an acquired change in tolerance. That is, within the same individual, as a result of repeated exposure to the drug, the same dose of the drug may produce a diminishing effect so that an increased amount of the drug is required to produce the same specified degree of effect.

Tolerance develops at differential rates to given effects of the same drug. If tolerance has developed to one specific effect, it has not necessarily developed to other specific effects.

By definition, the development of tolerance is neither beneficial nor detrimental. If tolerance develops rapidly to the desired mental effect of a "high" but slowly to the behavioral or physical effects, rapid increase in dose would be necessary in order to have the desired effect, and progressive behavioral and physical disruption would be seen. This is the pattern for amphetamines.

However, if tolerance develops slowly or not at all to the desired mental effects but more rapidly to the behaviorally or physically disruptive effects, no dosage increase or only a slight one would be necessary and the unpleasant and undesired effects would progressively diminish.

With regard to marihuana, present indications are that tolerance does develop to the behaviorally and physically disruptive effects, in both animals and man, especially at high frequent doses for prolonged time periods. Studies in foreign countries indicate that very heavy prolonged use of very large quantities of hashish leads to the development of tolerance to the mental effects, requiring an increase in intake to reach the original level of satisfaction. However, for the intermittent use pattern and even the moderate use pattern, little evidence exists to indicate the development of tolerance to the desired "high," although the high may persist for a shorter time period. During the Boston free-access study, no change was apparent in the level of the high produced by a relatively large dose of the drug over a 21-day period of moderate to heavy smoking.

The fact that some individuals smoke more of the drug than others may merely reflect a desire for a different level of "high." There is a tendency to develop a tolerance to the physical effects and behaviorally disruptive effects, especially the depressant effects, in heavy daily users. The development of such behavioral tolerance of this nature may explain the fact that experienced marihuana smokers describe a lower occurrence rate of undesirable drug effects. The development of tolerance may also explain why these smokers exhibit normal behavior and competent performance of ordinary tasks, while not appearing intoxicated to others even though they are at their usual level of intoxication.