peared to become tolerant to many of its initial effects, including memory disruption, decreased movement, and pain relief.17

Research also indicates that target cells for THC—those that bear CB1 and CB2 receptors—adapt to chronic THC exposure in ways that contribute to tolerance. Most studies of brain cells detected a decrease in the production of cannabinoid receptors under conditions that mimicked prolonged exposure to cannabinoids. Tolerance to cannabinoids appears to develop at different rates in different regions of the brain, however, which may explain why a few such studies have not found a decline in cannabinoid receptors. This phenomenon could also explain why tolerance to some effects of THC develops more quickly than to other effects. And in addition to their effects on CB1 and CB2 receptors, cannabinoids may have a desensitizing effect on other proteins in target cells.

Although intriguing, the results of these and other basic studies on the effects of cannabinoids should be interpreted with caution. Most basic studies consist of short-term experiments that merely simulate long-term marijuana use by exposing animals to higher amounts of cannabinoids than typically experienced by marijuana users. Moreover, cannabinoids behave differently in the human body depending on whether they are inhaled, injected, or swallowed. While most people ingest cannabinoids by smoking, they are generally injected into laboratory animals. Still, some of the same biochemical responses to chronic cannabinoid exposure that have been observed in experimental animals probably occur in humans as well, though perhaps in subtler forms.

Withdrawal from either marijuana or THC has been shown to cause several distinct symptoms, as reported by participants in clinical studies and adolescents undergoing treatment for substance abuse. These include restlessness, irritability, mild agitation, insomnia, sleep disturbance, nausea, and cramping—uncomfortable sensations, to be sure, but far milder than symptoms associated with alcohol withdrawal (see Table 3.1). Following very high doses of oral THC—the equivalent of smoking between five and 10 joints of average potency per day for 10 to 20 days—withdrawal symptoms also included runny nose, sweating, and decreased appetite, but lasted only four days. 18 In another study,



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