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Marijuana and the Human Brain

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.

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.

by Jon Gettman
High Times, March 1995


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.
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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.
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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.
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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.
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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 that most pharmaceutical companies years ago were afraid to get into that field. Companies were 'burnt' working on amphetamines and LSD. . . . They are afraid of notoriety."
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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.
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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.
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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.
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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.
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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.
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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.
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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."
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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."
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