"Marijuana, it turns out, affects brain chemistry in a qualitatively different way than addictive drugs.
Drugs of abuse such as heroin, cocaine, amphetamines, alcohol and nicotine affect the production of dopamine, an important neurotransmitter which chemically activates switches in the brain that produce extremely pleasurable feelings. Drugs that affect dopamine production produce addiction because the human brain is genetically conditioned to adjust behavior to maximize dopamine production. This chemical process occurs in the middle-brain, in an area called the striatum, which also controls various aspects of motor control and coordination.
Dr. Miles Herkenham of the National Institute of Mental Health (NIMH) and his research teams have made the fundamental discoveries behind these findings, and finally contradicted well-known marijuana cynic Gabriel Nahas of Columbia University. Supported in the 1980s by the antidrug group Parents Research Institute for Drug Education (PRIDE), Nahas has long argued that marijuana affects the middle-brain, justifying its prohibition.
Now Herkenham and his associates have proven that marijuana has no direct effect on dopamine production in the striatum, and that most of the drug's effects occur in the relatively "new" (in evolutionary terms) region of the brain - the FRONTAL CEREBRAL CORTEX. There is now biological evidence that far from being the "gateway" to abusive drugs, marijuana is instead the other way to get high - the safe way..."
"Brain receptor sites act as switches in the brain. The brain's neurotransmitters, or drugs which mimic them, throw the switches. The basic theory of tolerance is that repeated use of a drug wears out the receptors, and makes it difficult for them to function in the drug's absence. Worn-out receptors were supposed to explain the connection of tolerance to addiction. This phenomenon has been associated with chronic use of benzodiazepines (Valium, Prozac, etc.), for example, but not with cannabinoids."
"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."
"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 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."
"The NIMH tolerance study confirms what most marijuana smokers have already discovered for themselves: The more often you smoke, the less high you get."
"People who like to get "high" tend to smoke more often, and maintain modest tolerance to the depressant effects. But this is not an indefinite continuum. Just as joggers encounter limits, regular users of marijuana eventually confront the wall of receptor down-regulation. Smoking more pot doesn't increase the effects of the drug; it diminishes them."
"Like responsible alcohol drinkers, most marijuana users adjust the amount of marijuana they consume - they "titrate" it - according to its potency. In the course of a single day, for example, the equilibrium is between the amount consumed and the potency of the herb. Tolerance achieves the same equilibrium; over time the body compensates for prolonged exposure to THC by reducing the number of receptors available for binding. The body itself titrates the THC dose."
"Herkenham's earlier research mapping the locations of the cannabinoid brain-receptor system helped establish scientific evidence that marijuana is nonaddictive. This new tolerance study builds on that foundation by explaining how cannabinoid tolerance supports rather than contradicts that finding.
"It is ironic that the magnitude of both tolerance (complete disappearance of the inhibitory motor effects) and receptor down-regulation (78% loss with high-dose CP-55,940) is so large, whereas cannabinoid dependence and withdrawal phenomena are minimal. This supports the claim that tolerance and dependence are independently mediated in the brain."
In other words, tolerance to marijuana is not an indication that the drug is addictive."