Herkenham's research continued, and subsequently discovered the mechanism of tolerance to marijuana.

Tolerance describes an adaptation by the brain to the continued presence of a drug in which higher doses of the drug are required to obtain the effect of the initial dose.

The classic model holds that tolerance contributes to the development of dependence, and that withdrawal symptoms reflect the brain's inability to function without the accustomed drug. In this model the withdrawal symptoms are supposed to be the opposite of the drug's effects. (27)

Gabriel Nahas has written about the cell membrane paradigm for describing marijuana's effects since the early 1970's. His views have been very popular. Dr. Nahas originally held that marijuana users do not develop physical dependence identifiable with a specific withdrawal symptom. (28) Later he characterized withdrawal from marijuana as mild and not always clinical noticeable. (29) In 1990 withdrawal symptoms were described this way:

"Interruption of the regular use of marijuana is associated with an abstinence syndrome which is characterized by irritability, uneasiness and anxiety; nausea, diarrhea and sweating have also been reported. These symptoms are much less severe than those accompanying withdrawal from opiates which are quite unpleasant and anxiety laden resembling a very bad bout of flu."(30)

According to Abood and Martin:

"Under the most intense exposure regimen, the symptoms of withdrawal are relatively mild in most subjects. There are few reports in which the abrupt interruption in marijuana use has led to incapacitation of the individual abusing the substance. The number of people who have difficulty in controlling their abuse of cannabis to the extent that they require professional treatment is relatively small."(31)

Regardless on any link to withdrawal symptoms, some tolerance to marijuana does develop after regular, heavy use of the drug. (32)

Tolerance is not a simple phenomenon, and only recently have its various mechanisms been described in the literature. Depending on the mechanism involved, three categories of tolerance can be distinguished. Dispositional tolerance results from a change in absorption of the drug. Pharmacodynamic tolerance arises from adaptational changes in the brain. Behavioral tolerance results from familiarity with the environment in which the drug is administered. (33)

Dynamic tolerance also consists of subgroups, depending on the actual mechanism involved. According to one review:

"[A] number of adaptive processes can occur following repeated exposure to psychotropic drugs. In isolated tissues and cells, continuous exposure to some agonists (e.g. nicotine, opiates, and [benzodiazipines]) can produce a rapid desensitization . . . In brain tissue dissected from tolerant animals, downregulation of receptors and receptor uncoupling have been observed. The latter effect would appear to be a promising candidate for explaining tolerance to the effects of a number of psychotropic drugs. However, it is likely that no single neuronal adaptive process can account for the behavioral tolerance observed in vivo."(34)

The Nahas paradigm includes the hypothesis that tolerance to marijuana can be described as "metabolic tolerance arising from decreased sensitivity of the target cells."(35)

Through the use of autoradiographic assays, in 1993 Herkenham and his team discovered that tolerance to marijuana was produced by receptor down regulation. (36)

The objective of this study was to explain the following conclusions the authors drew from pharmacological literature:

"[E]xperienced users are capable of consuming enormous quantities of the drug with few or no obvious ill effects. Scores in cognitive tasks, both in human and non-human primate studies, show a paucity of measurable effects associated with chronic use . . . tolerance to most psychoactive and physiological effects does occur in humans when high doses are administered daily."(37)

At the observational level, the animals in this experiment who received the most potent doses of cannabinoids developed tolerance the quickest, and returned soonest to normal levels of activity.

At the neuronal level, quantifiable reductions in the density of cannabinoid receptors were observed that correlated with the behavioral responses. The results were very dramatic.

"[Indications of receptor regulation in other neuronal systems] stand in stark contrast to the massive and homogeneous changes in cannabinoid receptor levels found in the present [animal] study. The magnitude of the present effect, like the striking behavioral tolerance, may stem in part that, unlike other psychoactive agonist drugs, cannabinoids can be administered in very high doses. It is ironic that the magnitude of both tolerance (complete disappearance of the inhibitory motor effect) and receptor down-regulation (78% loss . . .) is so large, whereas cannabinoid dependence and withdrawal phenomena are minimal. This supports the claim (38) that tolerance and dependence are independently mediated in the brain."(39)

The conclusion of Herkenham's team on tolerance to cannabis is that:

"The effect is selective to D9-THC (ruling out changes in second messengers), is time- and dose-dependent, and is reversible, and thus appears to be cannabinoid-receptor mediated. We propose by extension that cannabinoid tolerance in vivo results, in [addition to behavioral factors], from cannabinoid receptor down-regulation."(40)

These 1993 findings of Herkenham dispute the claim that tolerance to marijuana is the result of desensitized brain cells worn out from excessive exposure to accumulated cannabinoids.