CHARACTERISTICS OF TETRAHYDROCANNABINOL TOLERANCE *

Tolerance to a drug is said to have developed “when, after repeated administration, a given dose of a drug produces a decreasing effect, or conversely when increasingly larger doses must be administered to obtain the effects observed with the original dose. ”’ There is evidenv that tolerance develops to the effects of marijuana and its active constituents in animaW6 and in man.7 However, many investigators have not observed tolerance to marijuana or its active constituents in animalss and in mang-lls or have suggested that the repeated administration of marijuana may result in an increased sensitivity to the subjective effects of marijuana in man.12 There are many factors that might have contributed to the conflicting findings concerning the development of tolerance to marijuana. Among the most serious of these factors has been the difficulty in controlling the dose level of the active constituents in marijuana, due to the varying purity of the preparations from the plant material.I3 Since tolerance to a drug is defined either in terms of a diminishing response to a constant dose or in terms of a constant response to graded increases in the dose, failure to control the dose adequately makes the demonstration of tolerance difficult. Other problems in demonstrating tolerance to marijuana and its active constituents may arise from differences in the methods used to assess tolerance and from species differences. We have attempted to minimize these problems by using only those constituents of marijuana that have been shown to have activity in man14-17 and are available in relatively pure form,ls and by using standardized procedures for measuring the development of tolerance in several species. Recently, schedule-controlled behavior has been used as a sensitive and stable baseline for assessing the development of tolerance to a number of d r ~ g s ~ * ~ J ~ ~ ~ in several species. The basic techniques for studying schedule-controlled behavior are well known.22 In our experiments, pigeons are trained to peck a translucent plastic response key in order to obtain a four-second access to mixed grain. Each peck breaks an electrical circuit, which permits the peck to be counted and recorded. Occasionally, depending on the schedule of food reward, pecks produce access to grain. The reward schedule for pigeons that has been used most often in tolerance s t ~ d i e s ~ ~ J ~ is the multiple fixed-ratio 30-response, fixed-interval fiveminute (mult FR 30 FI 5) schedule of food presentation. Under this schedule, when a blue light behind the translucent key is on, 30 key pecks are required to produce food (FR 30 component), and when a red light behind the key is on, the first key peck after five minutes produces food (FI 5 component). The two schedule components alternate throughout a session, with a 40-second time limit applying to both components of the schedule, so that the schedule can change automatically from one component to the other component if the pigeon is not responding at the time food is available. At these schedule parameters, pigeons usually respond at a high steady rate under the FR component, while responding under the FI 5 component is characterized by a pause early in the interval, followed by an increasing rate of responding as the availability of food appr0aches.2~