Marijuana and the Brain, The Tolerance Factor

by Jon Gettman
High Times, March 1995

In 1970, marijuana was placed on Schedule 1 of the Drug Enforcement Administration’s controlled-substances list, largely because scientists feared that, like opiates, it had an extremely high potential for abuse and addiction. But the discovery of THC receptor sites in the brain refutes that thinking, and may force both scientists and the DEA to re-evaluate their positions.

The next century will view the 1988 discovery of the THC receptor site in the brain as the pivotal event which led to the legalization of marijuana.

Before this discovery, no one knew for sure just how the psychoactive chemical in marijuana worked on the brain. Throughout the 1970s and 1980s, researchers made tremendous strides in understanding how the brain works, by using receptor sites as switches which respond to various chemicals by regulating brain and body functions.

The dominant fear about marijuana in the 20th century has been that its effects were somehow similar to the dangerously addictive effects of opiates such as morphine and heroin. Despite widespread decriminalization of marijuana in the United States in the 1970s, this concern has remained the basis for federal law and policies regarding the use and study of marijuana.

The legal manifestation of this fear is the continued classification of marijuana as a Schedule I drug, a category shared by heroin and other drugs that are banned from medical use because of their dangerous, addictive qualities. While only 11 states have formally decriminalized possession of small amounts of marijuana, 45 states distinguish between marijuana and other Schedule I drugs for law-enforcement and sentencing purposes.

Until the 1980s, technological limitations obstructed scientific understanding of the neuropharmacology of THC, of how the active ingredient in marijuana actually affects brain functions. Observations and conclusions about this subject, though based on some biological studies, were largely influenced by observations of behavior. This has allowed cultural prejudice to sustain the faith that marijuana is somehow related to heroin, and that research will eventually prove this hypothesis. Actually, the discovery of the THC receptor site and the subsequent research and observations it has inspired conclusively refute the hypothesis that marijuana is dope.

Many important brain functions which affect human behavior involve the neurotransmitter dopamine. Serious drugs of abuse, such as heroin and cocaine, interfere with the brain’s use of dopamine in manners that can seriously alter an individual’s behavior. A drug’s ability to affect the neural systems related to dopamine production has now become the defining characteristic of drugs with serious abuse potential.

According to the congressional Office of Technology Assessment, research over the last 10 years has proved that marijuana has no effect on dopamine-related brain systems – unless you are an inbred Lewis rat (see below), in which case abstention is recommended.

The discovery of a previously unknown system of cannabinoid neural transmitters is profound. While century-old questions, such as why marijuana is nontoxic, are finally being answered, new, fascinating questions are emerging – as in the case of all great discoveries. In the words of Israeli researcher Raphael Mechoulam, the man who first isolated the structure of THC, “Why do we have cannabinoid receptors?”

Mechoulam’s theory will resonate well with marijuana smokers in the United States. He observes that “Cannabis is used by man not for its actions on memory or movement coordination, but for its actions on memory and emotions,” and asks, “Is it possible that the main task of cannabinoid receptors . . . (is) to modify our emotions, to serve as the links which transmit or transform or translate objective or subjective events into perceptions and emotions?” At a 1990 conference on cannabinoid research in Crete, Mechoulam concluded his remarks by saying, “Let us hope, however, that through better understanding of cannabis chemistry in the brain, we may also approach the chemistry of emotions.”

The receptor breakthrough occurred in 1988 at the St. Louis University Medical School where Allyn Howlett, William Devane and their associates identified and characterized a cannabinoid receptor in a rat brain. The breakthrough has a long history leading up to it.

Major figures in American and British organic chemistry, such as Roger Adams, Alex Todd and Sigmund Loewe, did important work in determining the pharmacology of cannabis in the 1940s and 1950s, but their work ground to a halt due to the disinterest cultivated by the 1937 federal ban on marijuana. While synthetic compounds were created which were close to the actual compound, THC, they were not equivalent to it. The structure of one related chemical, cannabidiol, was determined.

After repeating the isolation of cannabidiol, in 1963 Mechoulam began work with Yehiel Gaoni that led to the determination of the biosynthetic pathway by which the plant synthesizes cannabinoids. In 1964 Gaoni and Mechoulam isolated tetrahydrocannabinol (THC) and a few years later they reported the first synthesis of THC.

Following the identification of the active constituent in marijuana, scientific research began to fill in the gaps and build on Mechoulam’s initial breakthrough. The neutral and acidic cannabinoids in cannabis were isolated, and their structures were elucidated. The absolute configurations were determined, as was a reasonable scheme of biogenesis. Total synthesis of the chemical was obtained, and the structure-activity relationship was established. These developments laid the foundation for pharmacological research involving animals and man.

This work, along with observations of marijuana’s therapeutic applications, opened up investigation into the medical properties of cannabinoids in general and THC in particular.

Medical research into the health effects of cannabis also matured throughout this period. In a comprehensive 1986 article in the Pharmacological Review, Leo Hollister of the Stanford University School of Medicine concluded that “compared with other licit social drugs, such as alcohol, tobacco and caffeine, marijuana does not pose greater risks.” Hollister wondered if these currently licit drugs would have enjoyed their popular acceptance based on our current knowledge of them. Nonetheless, it has been widely held throughout the 1980s, as Hollister concluded, that “Marijuana may prove to have greater therapeutic potential than these other social drugs, but many questions still need to be answered.”

The primary question, though, was how do cannabinoids work on the brain? By 1986, scientists were already on the slippery slope that would lead to the discovery of the cannabinoid receptor. The triennial reports from the National Institute on Drug Abuse summarizing research on marijuana had begun to omit references to research on marijuana-related brain damage and instead focus on brain receptor research. A comprehensive article by Renee Wert and Michael Raoulin was published in the International Journal of the Addictions that year, detailing the flaws in all previous studies that claimed to show brain damage resulting from marijuana use. As Hollister independently concluded, “Brain damage has not been proved.” The reason, obviously, is that the brain was prepared in some respects to process THC.

Also in 1986, Mechoulam put together a book reviewing this research, Cannabinoids as Therapeutic Agents (CRC Press, Boca Raton, FL). One promising area of research was the use of cannabinoids as analgesics or painkillers. A synthetic cannabinoid named CP 55,940, 10-100 times more potent than THC, was also developed in 1986; this was the key to the cannabinoid receptor breakthrough.

Receptors are binding sites for chemicals in the brain, chemicals that instruct brain cells to start, stop or otherwise regulate various brain and body functions. The chemicals which trigger receptors are known as neurotransmitters. The brain’s resident neurotransmitters are known as endogenous ligands. In many instances, drugs mimic these natural chemicals working in the brain. Scientists are just now confirming their determinations as to which endogenous ligands work on the cannabinoid receptors; it is likely that the neurotransmitter which naturally triggers cannabinoid receptors is one known as anandamide. Research continues.

To grossly oversimplify the research involved, a receptor is determined by exposing brain tissue to various chemicals and observing if any of them uniquely bind to the tissue. The search for a cannabinoid receptor depended on the use of a potent synthetic that would allow observation of the binding. CP 55,940 provided this potency, and it allowed Howlett, Devane and their associates, working with tissue from a rat brain, to fulfill precise scientific criteria for determining the existence of a pharmacologically-distinct cannabinoid in brain tissue.

A year later the localization of cannabinoid receptors in human brains and other species was determined by scientists at the National Institute of Mental Health, led by Miles Herkenham and including Ross Johnson and Lawrence Melvin, who had worked with Howlett and Devane on the earlier study.

The locations of the cannabinoid receptors are most revealing of the way THC acts on the brain, but the importance of this determination is best understood in comparison with the effects of other drugs on the brain.

Neurons are brain cells which process information. Neurotransmitter chemicals enable them to communicate with each other by their release into the gap between the neurons. This gap is called the synapse. Receptors are actually proteins in neurons which are specific to neurotransmitters, and which turn various cellular mechanisms on or off. Neurons can have thousands of receptors for different neurotransmitters, causing any neurotransmitter to have diverse effects in the brain.

Drugs affect the production, release or re-uptake (a regulating mechanism) of various neurotransmitters. They also mimic or block actions of neurotransmitters, and can interfere with or enhance the mechanisms associated with the receptor.

Dopamine is a neurotransmitter which is associated with extremely pleasurable sensations, so that the neural systems which trigger dopamine release are known as the “brain reward system.” The key part of this system is identified as the mesocorticolimbic pathway, which links the dopamine-production area with the nucleus of accumbens in the limbic system, an area of the brain which is associated with the control of emotion and behavior.

Cocaine, for example, blocks the re-uptake of dopamine so that the brain, lacking biofeedback, keeps on producing it. Amphetamines also block the re-uptake of dopamine, and stimulate additional production and release of it.

Opiates activate neural pathways that increase dopamine production by mimicking opioid-peptide neurotransmitters which increase dopamine activity in the ventral tegmental area of the brain where the neurotransmitter originates. Opiates work on three receptor sites, and in effect restrain an inhibitory amino acid, gamma-aminobutyric acid, that otherwise would slow down or halt dopamine production.

All of these substances can produce strong reinforcing properties that can seriously influence behavior. The rewarding properties of dopamine are what accounts for animal studies in which animals will forgo food and drink or willingly experience electric shocks in order to stimulate the brain reward system. It is now widely held that drugs of abuse directly or indirectly affect the brain reward system. The key clinical test of whether a substance is a drug of abuse potential or not is whether administration of the drug reduces the amount of electrical stimulation needed to produce self-stimulation response, or dopamine production. This is an indication that a drug has reinforcing properties, and that an individual’s use of the drug can lead to addictive and other harmful behavior.

To be precise, according to the Office of Technological Assessment (OTA): “The capacity to produce reinforcing effects is essential to any drug with significant abuse potential.”

Marijuana should no longer be considered a serious drug abuse because, as summarized by the OTA: “Animals will not self-administer THC in controlled studies . . . . Cannabinoids generally do not lower the threshold needed to get animals to self-stimulate the brain regard system, as do other drugs of abuse.” Marijuana does not produce reinforcing effects.

The definitive experiment which measures drug-induced dopamine production utilizes microdialysis is live, freely-moving rats. Brain microdialysis has proven that opiates, cocaine, amphetamines, nicotine and alcohol all affect dopamine production, whereas marijuana does not.

This latest research confirms and explains Hollister’s 1986 conclusion about cannabis and addiction: “Physical dependence is rarely encountered in the usual patterns, despite some degree of tolerance that may develop.”

Most important, the discoveries of Howlett and Devane, Herkenham and their associates demonstrate that the cannabinoid receptors do not influence the dopamine reward system.

Research has enabled scientists to know which portions of the brain control various body functions, and this knowledge has been used to explain the pharmacological properties of drugs that activate receptor sites in the brain.

There is a dense concentration of cannabinoid binding sites in the basal ganglia and the cerebellum of the base-brain, both of which affect movement and coordination. This discovery will aid in determining the actual physical mechanism by which THC affects spasticity and provides therapeutic benefits to patients with multiple sclerosis and other spastic disorders.

While there are cannabinoid receptors in the ventromedial striatum and basal ganglia which are areas associated with dopamine production, no cannabinoid receptors have been found in dopamine-producing neurons, and as mentioned above, no reinforcing properties have been demonstrated in animal studies.

There is one study by Gardner and Lowinson, involving inbred Lewis rats, in which doses of THC lowered the amount of electrical stimulation required to trigger the brain reward system. However, no one has been able to replicate the results with any other species of rat, or any other animal. The finding is believed to be the result of some inbred genetic variation in the inbred species, and is both widely mentioned in the literature and disregarded.

According to Herkenham and his associates, “There are virtually no reports of fatal cannabis overdose in humans. The safety reflects the paucity of receptors in medullary nuclei that mediate respiratory and cardiovascular functions.” This is also why cannabinoids have great promise as analgesics or painkillers, in that they do not depress the function of the heart or the lungs. In this respect, they are far superior to opiates, which decrease the entire physiological system because the receptors are all over the medulla as well as the brain.

Marijuana is distinguished from most other illicit drugs by the locations of its brain-receptor sites for two predominant reasons: (1) The lack of receptors in the medulla significantly reduces the possibility of accidental, or even deliberate, death from THC, and (2) the lack of receptors in the mesocorticolimbic pathway significantly reduces the risks of addiction and serious physical dependence. As a therapeutic drug, these features are God’s greatest gifts.

Mechoulam regrets that more has not been done in the therapeutic application of THC. In a 1986 interview with the International Journal of the Addictions, he said that, “Knowing what I know today, I would have worked more on the therapeutic aspects of cannabis. This area apparently needs a major push that is has not had up till now, particularly given that it has a therapeutic potential. One of the reasons that it has not been pushed was that most pharmaceutical companies years ago were afraid to get into that field. Companies were ‘burnt’ working on amphetamines and LSD. . . . They are afraid of notoriety.”

Clearly, cannabis acts on coordination of movement by way of the receptors in the cerebellum and basal ganglia, and on memory by way of the receptors in the limbic system’s hippocampus, which “gates” information during memory consolidation. Mechoulam believes that in humans these actions “are rather marginal.”

“Cannabis,” he states, “is used . . . for its actions on mood and emotion.” The key to understanding the reason for the presence of cannabinoid receptors in the human brain lies in understanding the role of the receptors in the limbic system, which has a central role in the mechanisms which govern behavior and emotions.

The limbic system coordinates activities between the visceral base-brain and the rest of the nervous system. “We know next to nothing on the chemistry of emotions,” Mechoulam instructs. It is his hope that future research on the role of cannabinoid receptors in the brain will shed light on this new area of investigation and reflection.

Advances in neurobiology are redefining the scientific basis for addiction. These advances have important ramifications for addiction treatment, and for the treatment of numerous organic diseases and conditions. More importantly for marijuana users, these advances in neurobiology will ultimately force changes in the law.

The law is constantly being modified in response to technological changes. The passage of the Controlled Substances Act in 1972 was in part due to a greater understanding of drug abuse brought about by the medical research of the time.

The law instituted a policy by which regulation and criminal penalties regarding controlled substances were to be correlated with the harmfulness of the substance. Specifically, the law lists the “actual or relative potential for abuse” as the first matter to be considered in determining the appropriate scheduling of a drug. Schedule I is for drugs which have a “high potential for abuse.”

While the scheduling of marijuana and its subsequent availability for research and medical use was the subject of a 22-year unsuccessful court battle spearheaded by the National Organization for the Reform of Marijuana Laws, the question of marijuana’s abuse potential was never addressed during the litigation and related proceedings. The suit over medical marijuana sought to reschedule marijuana as a Schedule II drug, which also implies a “high potential for abuse.” This made the abuse question irrelevant to the court proceedings.

However, the abuse question is the pre-eminent issue in attempts to reform marijuana laws, and it is the weak link upon which the entirety of marijuana prohibition rests. The most recent research indicates that marijuana does not have a high potential for abuse, especially relative to other scheduled drugs such as heroin, cocaine, sedatives and amphetamines.

The medical-marijuana petition was rejected by the administrator of the DEA because of the lack of scientific studies detailing marijuana’s medical value. The court appeal essentially concerned whether or not this was a reasonable standard in light of the government’s historic disinterest in funding such studies. While courts have ruled that DEA can rely on research studies, or the lack thereof, in its decision-making about the scheduling of marijuana, they have not ruled on the actual issues which determine the proper legal scheduling of marijuana.

The discovery of cannabinoid receptor sites, and their relevance to the understanding of the pharmacology of THC in the brain, provides the basis for a new challenge to the legitimacy of marijuana’s Schedule I status, a pivotal event in marijuana’s eventual legalization.


Reprinted without permission from High Times, which probably doesn’t really mind. For subscription or other information e-mail

Marijuana and the Brain, Part II:
The Tolerance Factor

The architects of marijuana prohibition have long maintained that tolerance to cannabis means the same thing as tolerance to addictive drugs like cocaine and heroin – that users need more and more to get high, driving them to crime and desperation. Now, the federal government’s own research indicates that precisely the opposite is true. Science has finally caught on to what tokers have known all along: With marijuana tolerance, you have to smoke less to get high! High Times correspondent Jon Gettman explains the latest findings and how they discredit the government’s drug policy.

by Jon Gettman
High Times, July 1995

One of the safest qualities of THC, delta-9 tetrahydrocannabinol, the primary psychoactive substance in marijuana, is the natural limit the body places on the drug’s effects.

It has long mystified scientists how most individuals can consume enormous quantities of marijuana with few or no obvious ill effects. But the explanation will not surprise regular marijuana users.

Early researchers were often alarmed by this, believing that this tolerance was a warning sign of dependence or addiction. Tolerance generally describes the condition of requiring larger doses of a drug to attain consistent effects. While tolerance to marijuana has never exactly fit the classic definition, some form of tolerance to pot does develop.

Regular users of marijuana frequently claim that this tolerance reduces troublesome side effects, such as loss of coordination. They also claim that tolerance to marijuana develops without risk of dependence.

Cynics have argued that tolerance to marijuana is proof of dependence, and proof that the drug is too dangerous to be used safely and responsibly.

Science has finally proven otherwise. The cynics have been wrong, the pot-smokers have been right. Tolerance to marijuana is not an indication of danger or dependence.

This conclusion also adds credence to anecdotal accounts of marijuana’s therapeutic benefits by patients suffering from serious illnesses.

The recent discovery of a cannabinoid receptor system in the human brain has revolutionized research on marijuana and cannabinoids, and definitively proven that marijuana use does not have a dependence or addiction liability (“Marijuana and the Human Brain,” March 1995 High Times). 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.

The effects of marijuana share certain properties with all the other psychoactive drugs – stimulants, sedatives, tranquilizers and hallucinogens. Scientists are just now figuring out how marijuana users manipulate dosage and tolerance to manage those effects.

Small doses of THC provide stimulation, followed by sedation. Large doses of THC produce a mild hallucinogenic effect, followed by sedation and/or sleep. The effects of mild “hypnogogic” states produced by THC are often undetected, contributing to mood variations from gregariousness to introspection.

The effects of marijuana can be sorted into four categories. First, there are modest physical effects, such as a slight change in heart rate or blood pressure and changes in body temperature. Tolerance develops to these effects with familiarity and/or regular use.

Tolerance next develops to the depressant effects of marijuana, particularly to its effects on motor coordination. However, tolerance to these effects depends on the quality of the marijuana consumed as well as the frequency of use. THC is one of several cannabinoids in marijuana. While it is the only cannabinoid to produce the psychoactive or stimulative effects, another cannabinoid, named cannabinol (CBN), produces only the depressant effects. CBN is generally present in low-potency marijuana, or very old marijuana in which the THC has decayed; it accounts for the generally undesirable effects of bad pot. While cannabinol gets someone “stoned,” THC gets them “high.”

After a while, tolerance develops to even the stimulative effects of marijuana. Experienced users learn that there is an outer limit to how high they can get. Paradoxically, this limit can only be exceeded by lower consumption.

Patients who require marijuana for medical purposes generally discover what dose provides steady maintenance of therapeutic benefits and tolerance to the side effects, both depressant and stimulative.

Research into drug tolerance is in its infancy. There are actually three forms of tolerance. Dispositional tolerance is produced by changes in the way the body absorbs a drug. Dynamic tolerance is produced by changes in the brain caused by an adaptive response to the drug’s continued presence, specifically in the receptor sites affected by the drug. Behavioral tolerance is produced by familiarity with the environment in which the drug is administered. “Familiarity” and “environment” are two alternative terms for what Timothy Leary called “set” and “setting” – the subjective emotional/mental factors that the user brings to the drug experience and the objective external factors imposed by their surroundings. Tolerance to any drug can be produced by a combination of these and other mechanisms.

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.

An alternative hypothesis about how dynamic tolerance to marijuana operates involves receptor “down-regulation,” in which the body adjusts to chronic exposure to a drug by reducing the number of receptor sites available for binding. A 1993 paper published in Brain Research by Angelica Oviedo, John Glowa and Herkenham indicates that tolerance to cannabinoids results from receptor down-regulation. This, as we shall see, is good news. It means that marijuana tolerance is actually the brain’s mechanism to maintain equilibrium.

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.

The NIMH tolerance study confirms what most marijuana smokers have already discovered for themselves: The more often you smoke, the less high you get.

The dose of THC used in the study was 10 mg per kilogram of body weight, a dose frequently used in clinical research. What is the equivalent of 10 mg/kg of THC in terms of human consumption?

While most users are familiar with varying potencies of marijuana, many are only vaguely aware of differences in the efficiency of various ways to smoke it. Clinical studies indicate that only 10 to 20% of the available THC is transferred from a joint cigarette to the body. A pipe is better, allowing for 45% of the available THC to be consumed. A bong is a very efficient delivery system for marijuana; in ideal conditions the only THC lost is in the exhaled smoke.

The minimum dose of THC required to get a person high is 10 micrograms per kilogram of body weight. For a 165-pound person, this would be 750 micrograms of THC, about what is delivered by one bong hit.

The THC doses used on the NIMH rats were proportionately ten times greater than what a heavy human marijuana user would consume in a day. Assuming use of good-quality, 7.5% THC sinsemilla, it would take something like 670 bong hits or 100 joints to give a 165-pound person a 10 mg-per-kg dose of THC.

Obviously, the doses used are excessive. But the study indicates that the body itself imposes an unbeatable equilibrium on cannabis use, a ceiling to every high.

According to Herkenham’s team: “The result [of the study] has implications for the consequences of chronic high levels of drug use in humans, suggesting diminishing effects with greater levels of consumption.”

Tolerance and the quality of the marijuana both affect the balance between the two tiers of effects: the coordination problems, short-term memory loss and disorientation associated with the term “stoned” and the pleasurable sensations and cognitive stimulation associated with the word “high.”

The distinction between the two states is nothing unique. Alcohol, nicotine and heroin can all produce nausea when first used; this symptom also disappears as tolerance to the drug develops. To conclude that marijuana users consume the drug to get “stoned” would be as accurate as asserting that alcohol drinkers drink in order to vomit.

One result of the NIMH study is that there is now a clinical basis for characterizing the differences between these two tiers of effects. In clinical terms, the effects of one-time (or occasional) exposure are referred to as the acute effects of marijuana. Repeated use or exposure is referred to as chronic use.

In addition to the now-disproved claims of dependence, opponents of marijuana-law reform always refer to the acute effects of the drug as proof of its dangers. Prohibitionists believe that tolerance is evidence that marijuana users have to increase their consumption to maintain the acute effects of the drug. No wonder they think marijuana is dangerous!

Marijuana-law reform advocates, more familiar with actual use patterns and effects, always consider the effects of chronic use as their baseline for describing the drug. “Chronic use” is just regular use, and there is nothing sinister about regular marijuana use.

Most marijuana users regulate their use to achieve specific effects. The main technique for regulating the effects of marijuana is manipulating tolerance. Some people who like to get “stoned” on pot, which (unlike the initial side effects of other drugs) can be enjoyable. These people smoke only occasionally.

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.

The ideal state is right between the two tiers of effects. One of the great ironies of prohibition is that most marijuana users are left to figure this out for themselves. Most do, and strive for the middle ground. Some just don’t figure it out, and this explains two behaviors which are identified as marijuana abuse.

First is binge smoking, often but not exclusively exhibited by young or inexperienced users who mistakenly believe that they can compensate for tolerance with excessive consumption. The second behavior these new findings on tolerance explain is the stereotype of the stoned, confused hippie. According to this NIMH study, tolerance develops faster with high-potency cannabinoids. People who have irregular access to marijuana, and to low-quality marijuana at that, do not have the opportunity to develop sufficient tolerance to overcome the acute effects of the drug.

Another popular misconception this study contradicts is that higher-potency marijuana is more dangerous. In fact, the use of higher-potency marijuana allows for the rapid development of tolerance. Earlier research by Herkenham established why large doses of THC are not life-threatening. Marijuana’s minimal effects on heart rate are still mysterious, but there are no cannabinoid receptors in the areas of the brain which control heart function and breathing. This research further establishes that the brain can safely handle large, potent doses of THC.

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.

Norman Zinberg, in ‘Drug, Set and Setting’ (Yale, New Haven, CT, 1984), explained that the key to understanding the use of any drug is to realize that three variables affect the situation: drug, set and setting. It is now a scientific finding that the pharmacological effects of marijuana do not produce dependency. The use and abuse of marijuana is a function of behavior – interrelated psychological and environmental factors.

Addictive drugs affect behavior through their effects on the brain “reward system” – the production of dopamine, linked to the pleasure sensation. This brain “reward system” has a powerful influence over behavior. Dependence-producing drugs – drugs that, unlike marijuana, affect dopamine production – eventually exert more influence on the user’s behavior than any other factor. The effect of addiction on behavior is so profound as to create a condition called denial, in which someone will say or do anything to continue access to the drug.

Denial is a characteristic of drug abuse, and it is largely cultivated by the effects of various drugs on the brain reward system. Herkenham’s research provides a clinical basis for claims that denial is not a characteristic of marijuana use.

This is devastating to opposition to the medical use of marijuana, which is solely based on challenges to the credibility of personal observations by patients exploiting marijuana’s therapeutic benefits.

John Lawn, then-administrator of the DEA, had this to say in 1989 about the credibility of marijuana’s medicinal users when he rejected the recommendation of Administrative Law Judge Francis Young that marijuana be made available for medical use: “These stories of individuals who treat themselves with a mind-altering drug, such as marijuana, must be viewed with great skepticism…These individuals’ desire to rationalize their marijuana use removes any scientific value from their accounts of marijuana use.”

As a result of this new research at the National Institute of Mental Health, there is no scientific basis for that sort of prejudice on the part of our public servants. Just as marijuana users have been accurate in describing the tolerance and dependence liabilities of marijuana for over 20 years, patients who use marijuana medicinally are accurate in describing the therapeutic benefits they achieve with their marijuana use.

Constant therapeutic use of marijuana represents a third tier of effects from the drug, a tier once thought unimaginable because of the now-discredited fear of addiction. At this level, tolerance compensates for virtually all marijuana-related impairment of motor coordination and cognitive functions. The result is a therapeutic drug with wide applications and few debilitating side effects.

The outer limits of being high are reached when natural systems decide that the needs of the body supersede the wants of the mind. The third tier represents the most noble effects of marijuana: comfort, care and treatment for people with genuine needs.

The discovery of the cannabinoid receptor system was a revolutionary event of profound significance. These new findings on tolerance may presage further revolutionary developments from the laboratories of NIMH in the next few years – such as the natural role of the cannabinoid receptor system and the brain chemical which activates it.

Meanwhile, advocates of marijuana-law reform must learn to use the latest research as a tool to demonstrate that marijuana users have been right for a long, long time. The remaining challenge is to confront the irrationality of America’s current public policy.

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