Marijuana and the Human Brain

The N.I.M.H. tolerance study

Herkenham's team studied six groups of rats. They compared changes in behavioral responses with changes in the density of receptor sites in six areas of the brain. One group of rats was the control group, which were given the "vehicle" solution the other five rat groups received, but without any cannabinoids. In other words, the control rats got a placebo; the other rats got high. A second group was given cannabidiol (CBD), a non-psychoactive cannabinoid. The third group was given delta-9 THC. Three other groups were given different doses of a synthetic cannabinoid called CP-55,940, with a far greater ability to inhibit movement than delta-9 THC. CP-55-940, a synthetic isomer of THC, was developed as an experimental analgesic.

First, the study determined the effects of a single dose of each compound compared to the undrugged control group. Rats receiving the placebo and the CBD displayed no sign of effects. The animals receiving the psychoactive cannabinoids, THC and CP-55,940, "exhibited splayed hind limbs and immobility."

Anyone who has eaten too many pot brownies should have some idea of the condition of the rats after their initial doses. The human equivalency of the doses of THC used in this study would be in excess of a huge brownie overdose.

A single 10-milligram dose of nonpsychoactive CBD for a one-kg rat actually increased the density of receptor sites by 13% and 19% in two key areas of the brain: the medial septum/diagonal band region and the lateral caudate/putamen - both motor-control areas.

A single 10-mg dose of delta-9 THC had no change on receptor-site density. A single 10-mg dose of CP-55,940 produced a drop in the density of receptor sites, to 46% and 60% of the control group's levels.

The effect the drugs had on motor behavior was observed daily, and at the end of the study the rats were "sacrificed" (killed) and the density of the receptor sites in various areas of their brains was determined.

What effect did the daily injections have on the various rats' behavior? According to the researchers, "The animals receiving the highest dose of CP-55,940 tended to show more rapid return to control levels of activity than did the animals receiving the lowest dose, with the middle-dose animals in between."

The groups receiving CBD showed no changes in receptor-site density after 14 days. All the other groups exhibited receptor down-regulation of significant magnitudes.

The changes consistently followed a dose-response relationship, especially in regard to CP-55,940. The high-dose animals had the greatest decrease (up to 80%), the low-dose animals had the lowest reduction (up to 50%), and the middle-dose group exhibited an intermediate reduction (up to 72%). The delta-9 THC group exhibited receptor reductions of up to 48%, comparable to the lowest dose of CP-55,940.

The conclusions of the researchers: "It would seem paradoxical that animals receiving the highest doses of cannabinoids would show the greatest and fastest return to normal levels [of behavior]; however, the receptor down-regulation in these animals was so profound that the behavioral correlate may be due to the great loss of functional binding sites." In other words, when the rats had had "enough," their receptors simply switched off.

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