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.
The NIMH tolerance study confirms what most marijuana smokers have already