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MARIJUANA & THE BRAIN, PART II: THE TOLERANCE FACTORBy
Jon Gettman, July 1995 High Times
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!
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
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.
also adds credence to anecdotal accounts of marijuana's therapeutic benefits by
patients suffering from serious illnesses.
YOUR BRAIN IS PROGRAMMED TO PROCESS POT
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, 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.
THC: DOSE AND EFFECT
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.
MARIJUANA TOLERANCE: EQUILIBRIUM, NOT ADDICTION
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
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.
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 and got a placebo. 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
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
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.
HOW TO STAY HIGH: LESS IS MORE
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 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
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.
TOLERANCE, DEPENDENCE AND DENIAL
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.
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.
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
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.
THE POLICY IMPLICATIONS
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
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 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
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.
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.