From: [philsm t h] at [teleport.com] (Phil Smith)
Newsgroups: alt.hemp,alt.drugs.pot,alt.drugs,alt.hemp.politics,alt.hemp.recreational,alt.news-media,alt.psychedelics,talk.politics.drugs
Subject: High Times: "M. & the Human Brain"
Date: 10 Aug 1995 11:19:53 GMT

This is a fascinating and memorable explanation of why marijuana is NOT
addictive and is not a drug of abuse. The author, Jon Gettman, is a former
director of national Norml and July 10 1995 filed suit in federal court 
to have marijuana removed from the class of Schedule 1 (and Schedule 2) 
drugs. This article somewhat explains Gettman's legal case.

This was asciied by a friend and then carefully checked by myself. Two 
significant illustrations accompanied this article in its original format.
The first diagrams the mesocorticolimbic pathway and the second 
illustrates brain synapses & associated structures. Neither is essential 
to a full understanding of the article. 
Please email any corrections to [philsm t h] at [teleport.com] (a prize to the 
first person who emails me a decent ascii-art version of the original 
illustrations.)

Reprinted without permission from High Times, which probably doesn't 
really mind.
For subscription or other information email [h--t--s] at [echonyc.com]

MARIJUANA AND THE HUMAN BRAIN
by Jon Gettman
High Times
March 1995

In 1970, marijuana was placed on Schedule 1 of the Drug Enforcement 
Administrationís 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. 

Introduction

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 brainís use of dopamine in manners that can 
seriously alter an individualís behavior.  A drugís 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?"
Mechoulamís 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 of movement 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."


A BRIEF HISTORY OF THC RESEARCH
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 Mechoulamís 
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 marijuanaís 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 brainís 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.

RECEPTORS IN THE BRAIN
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 individualís 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 Hollisterís 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.

CANNABINOID RECEPTORS
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 Godís greatest gifts.


THE CHEMISTRY OF EMOTIONS
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 than most 
pharmaceutical companies years ago were afraid to get into that field. 
Companies were ëburntí 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 systemís 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.

THE FUTURE OF MARIJUANA LAWS
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 marijuanaís 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 marijuanaís 
medical value.  The court appeal essentially concerned whether or not 
this was a reasonable standard in light of the governmentís 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 marijuanaís Schedule 
I status, a pivotal event in marijuanaís eventual legalization.
(End)