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Marijuana and the Human Brain

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.

Read next part Receptors in the brain

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