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

Marijuana and the Brain, Part II - The Tolerance Factor

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.


Text file of this article

Author's addendum

Information about the acceptance of Gettman's petition in 1998..

Marijuana, Science, and Public Policy, an extensive collection of material prepared over the years by Jon Gettman about his rescheduling petition.

What about more recent reports marijuana increases dopamine production?

Reprinted without permission from High Times (though we did send them a message about it). For subscription or other information e-mail

Marijuana and the Human Brain (Part 1), by Jon Gettman


More information about addiction and dependence

Back to the Articles page.

This URL: