Marijuana & The Brain, Part Ii:

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
July 1995 'High Times'

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.

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 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.

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.

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.

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 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.

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, 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.

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 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.

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.

"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.

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 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.

\t\t\t[End]

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

***

Marijuana, Science, and Public Policy -

an extensive collection of material prepared over the years by Jon Gettman
about his rescheduling petition:

http://www.hightimes.com/ht/new/petition/JonGettman/AA/aamspp.htm
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