Tolerance to marijuana was supposed to the a manifestation of desensitization of brain cells, and in addition to contributing to the supposed dependence liability this desensitization of brain cells was supposed to create an amotivational syndrome characterized by apathy and inactivity. The hypothesis was that this desensitization would impede normal brain operations and render individuals somewhat sluggish and unmotivated. The hypothesis has been challenged on both behavioral and pharmacological grounds.

In a widely respected review of the literature in 1986, Leo Hollister addresses the issues raised by the amotivational syndrome hypothesis:

"Whether chronic use of cannabis changes the basic personality of the user so that he or she becomes less impelled to work and to strive for success has been a vexing question. As with other questions concerning cannabis use, it is difficult to separate consequences from possible causes of drug use . . . The demonstration of such a syndrome in field studies has been generally unsuccessful. . . Laboratory studies have provided only scant evidence for this concept . . .

"If this syndrome is so difficult to prove, why does concern about it persist? Mainly because of clinical observations. One cannot help being impressed by the fact that many promising youngsters change their goals in life drastically after entering the illicit drug culture, usually by way of cannabis. While it is clearly impossible to be certain that these changes were caused by the drug (one might equally argue that the use of drug followed the decision to change life style), the consequences are often sad. With cannabis as with most other pleasures, moderation is the key word. Moderate use of the drug does not seem to be associated with this outcome, but when drug use becomes a preoccupation, trouble may be in the offing."(41)

In 1992, Abood and Martin has little more to offer, and in fact base their conclusion on Hollister's 1986 paper and a review by Fehr and Kalant published in the 1983 proceedings of a World Health Organization meeting. Martin concludes in 1992 that:

"An 'amotivational syndrome' has been frequently described in the literature . . .Well controlled studies, however, have failed to provide strong evidence that an amotivational syndrome is a direct consequence of marijuana use."(42)

The hypothesis that the desensitization of brain cells caused by marijuana use explained both tolerance to the drug and an amotivational syndrome has been discredited by both natural and social science research.