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MARIJUANA AND THE HUMAN BRAIN
Jon Gettman, High Times, March 1995
In 1970, marijuana was placed on Schedule 1 of the Drug Enforcement Administration's
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. 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
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.
Serious drugs of abuse, such as heroin and cocaine, interfere with the brain's
use of dopamine in manners that can seriously alter an individual's behavior.
A drug's 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?"
Mechoulam's theory will resonate well with marijuana smokers. 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.
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.
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."
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
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 brain's
resident neurotransmitters are known as endogenous ligands. In many instances,
drugs mimic these natural chemicals working in the brain.
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 individual's 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
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
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 Hollister's 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
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, "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 God's greatest gifts.
THE CHEMISTRY OF EMOTIONS
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 system's hippocampus, which "gates" information during memory consolidation.
Mechoulam believes that in humans these actions "are rather marginal."
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 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 NORML, the question of marijuana's 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 marijuana's medical value. The court
appeal essentially concerned whether or not this was a reasonable standard in
light of the government's 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 marijuana's Schedule I status, a pivotal event in marijuana's