Marijuana pharmacology

Marijuana And the Brain
by John 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.

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 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 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 Mechoulam's 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 marijuana's 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 brain's 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 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 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 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 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 God's 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 'burnt' 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 system's 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 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 eventual legalization.
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