G
Guest
A long, but informative read.
The Brain's Own Marijuana
Research into natural chemicals that mimic marijuana's effects in the brain could help to explain--and suggest treatments for--pain, anxiety, eating disorders, phobias and other conditions
By Roger A. Nicoll and Bradley N. Alger
Marijuana is a drug with a mixed history. Mention it to one person, and it will conjure images of potheads lost in a spaced-out stupor. To another, it may represent relaxation, a slowing down of modern madness. To yet another, marijuana means hope for cancer patients suffering from the debilitating nausea of chemotherapy, or it is the promise of relief from chronic pain. The drug is all these things and more, for its history is a long one, spanning millennia and continents. It is also something everyone is familiar with, whether they know it or not. Everyone grows a form of the drug, regardless of their political leanings or recreational proclivities. That is because the brain makes its own marijuana, natural compounds called endocannabinoids (after the plant's formal name, Cannabis sativa).
The study of endocannabinoids in recent years has led to exciting discoveries. By examining these substances, researchers have exposed an entirely new signaling system in the brain: a way that nerve cells communicate that no one anticipated even 15 years ago. Fully understanding this signaling system could have far-reaching implications. The details appear to hold a key to devising treatments for anxiety, pain, nausea, obesity, brain injury and many other medical problems. Ultimately such treatments could be tailored precisely so that they would not initiate the unwanted side effects produced by marijuana itself.
A Checkered Past
Marijuana and its various alter egos, such as bhang and hashish, are among the most widely used psychoactive drugs in the world. How the plant has been used varies by culture. The ancient Chinese knew of marijuana's pain-relieving and mind-altering effects, yet it was not widely employed for its psychoactive properties; instead it was cultivated as hemp for the manufacture of rope and fabric. Likewise, the ancient Greeks and Romans used hemp to make rope and sails. In some other places, however, marijuana's intoxicating properties became important. In India, for example, the plant was incorporated into religious rituals. During the Middle Ages, its use was common in Arab lands; in 15th-century Iraq it was used to treat epilepsy; in Egypt it was primarily consumed as an inebriant. After Napoleon's occupation of Egypt, Europeans began using the drug as an intoxicant. During the slave trade, it was transported from Africa to Mexico, the Caribbean and South America.
Marijuana gained a following in the U.S. only relatively recently. During the second half of the 19th century and the beginning of the 20th, cannabis was freely available without a prescription for a wide range of ailments, including migraine and ulcers. Immigrants from Mexico introduced it as a recreational drug to New Orleans and other large cities, where it became popular among jazz musicians. By the 1930s it had fallen into disrepute, and an intense lobbying campaign demonized "reefer madness." In 1937 the U.S. Congress, against the advice of the American Medical Association, passed the Marijuana Tax Act, effectively banning use of the drug by making it expensive and difficult to obtain. Ever since, marijuana has remained one of the most controversial drugs in American society. Despite efforts to change its status, it remains federally classified as a Schedule 1 drug, along with heroin and LSD, considered dangerous and without utility.
Millions of people smoke or ingest marijuana for its intoxicating effects, which are subjective and often described as resembling an alcoholic "high." It is estimated that approximately 30 percent of the U.S. population older than 12 have tried marijuana, but only about 5 percent are current users. Large doses cause hallucinations in some individuals but simply trigger sleep in others. The weed impairs short-term memory and cognition and adversely affects motor coordination, although these setbacks seem to be reversible once the drug has been purged from the body. Smoking marijuana also poses health risks that resemble those of smoking tobacco.
On the other hand, the drug has clear medicinal benefits. Marijuana alleviates pain and anxiety. It can prevent the death of injured neurons. It suppresses vomiting and enhances appetite--useful features for patients suffering the severe weight loss that can result from chemotherapy.
Finding the Responsible Agent
Figuring out how the drug exerts these myriad effects has taken a long time. In 1964, after nearly a century of work by many individuals, Raphael Mechoulam of the Hebrew University in Jerusalem identified delta-9-tetrahydrocannabinol (THC) as the compound that accounts for virtually all the pharmacological activity of marijuana. The next step was to identify the receptor or receptors to which THC was binding.
Receptors are small proteins embedded in the membranes of all cells, including neurons, and when specific molecules bind to them--fitting like one puzzle piece into another--changes in the cell occur. Some receptors have water-filled pores or channels that permit chemical ions to pass into or out of the cell. These kinds of receptors work by changing the relative voltage inside and outside the cell. Other receptors are not channels but are coupled to specialized proteins called G-proteins. These G-protein-coupled receptors represent a large family that set in motion a variety of biochemical signaling cascades within cells, often resulting in changes in ion channels.
In 1988 Allyn C. Howlett and her colleagues at St. Louis University attached a radioactive tag to a chemical derivative of THC and watched where the compound went in rats' brains. They discovered that it attached itself to what came to be called the cannabinoid receptor, also known as CB1. Based on this finding and on work by Miles Herkenham of the National Institutes of Health, Lisa Matsuda, also at the NIH, cloned the CB1 receptor. The importance of CB1 in the action of THC was proved when two researchers working independently--Catherine Ledent of the Free University of Brussels and Andreas Zimmer of the Laboratory of Molecular Neurobiology at the University of Bonn--bred mice that lacked this receptor. Both investigators found that THC had virtually no effect when administered to such a mouse: the compound had nowhere to bind and hence could not trigger any activity. (Another cannabinoid receptor, CB2, was later discovered; it operates only outside the brain and spinal cord and is involved with the immune system.)
As researchers continued to study CB1, they learned that it was one of the most abundant G-protein coupled receptors in the brain. It has its highest densities in the cerebral cortex, hippocampus, hypothalamus, cerebellum, basal ganglia, brain stem, spinal cord and amygdala. This distribution explains marijuana's diverse effects. Its psychoactive power comes from its action in the cerebral cortex. Memory impairment is rooted in the hippocampus, a structure essential for memory formation. The drug causes motor dysfunction by acting on movement control centers of the brain. In the brain stem and spinal cord, it brings about the reduction of pain; the brain stem also controls the vomiting reflex. The hypothalamus is involved in appetite, the amygdala in emotional responses. Marijuana clearly does so much because it acts everywhere.
Over time, details about CB1's neuronal location emerged as well. Elegant studies by Tamás F. Freund of the Institute of Experimental Medicine at the Hungarian Academy of Sciences in Budapest and Kenneth P. Mackie of the University of Washington revealed that the cannabinoid receptor occurred only on certain neurons and in very specific positions on those neurons. It was densely packed on neurons that released GABA (gamma-aminobutyric acid), which is the brain's main inhibitory neurotransmitter (it tells recipient neurons to stop firing). CB1 also sat near the synapse, the contact point between two neurons. This placement suggested that the cannabinoid receptor was somehow involved with signal transmission across GABA-using synapses. But why would the brain's signaling system include a receptor for something produced by a plant?
continued...
The Brain's Own Marijuana
Research into natural chemicals that mimic marijuana's effects in the brain could help to explain--and suggest treatments for--pain, anxiety, eating disorders, phobias and other conditions
By Roger A. Nicoll and Bradley N. Alger
Marijuana is a drug with a mixed history. Mention it to one person, and it will conjure images of potheads lost in a spaced-out stupor. To another, it may represent relaxation, a slowing down of modern madness. To yet another, marijuana means hope for cancer patients suffering from the debilitating nausea of chemotherapy, or it is the promise of relief from chronic pain. The drug is all these things and more, for its history is a long one, spanning millennia and continents. It is also something everyone is familiar with, whether they know it or not. Everyone grows a form of the drug, regardless of their political leanings or recreational proclivities. That is because the brain makes its own marijuana, natural compounds called endocannabinoids (after the plant's formal name, Cannabis sativa).
The study of endocannabinoids in recent years has led to exciting discoveries. By examining these substances, researchers have exposed an entirely new signaling system in the brain: a way that nerve cells communicate that no one anticipated even 15 years ago. Fully understanding this signaling system could have far-reaching implications. The details appear to hold a key to devising treatments for anxiety, pain, nausea, obesity, brain injury and many other medical problems. Ultimately such treatments could be tailored precisely so that they would not initiate the unwanted side effects produced by marijuana itself.
A Checkered Past
Marijuana and its various alter egos, such as bhang and hashish, are among the most widely used psychoactive drugs in the world. How the plant has been used varies by culture. The ancient Chinese knew of marijuana's pain-relieving and mind-altering effects, yet it was not widely employed for its psychoactive properties; instead it was cultivated as hemp for the manufacture of rope and fabric. Likewise, the ancient Greeks and Romans used hemp to make rope and sails. In some other places, however, marijuana's intoxicating properties became important. In India, for example, the plant was incorporated into religious rituals. During the Middle Ages, its use was common in Arab lands; in 15th-century Iraq it was used to treat epilepsy; in Egypt it was primarily consumed as an inebriant. After Napoleon's occupation of Egypt, Europeans began using the drug as an intoxicant. During the slave trade, it was transported from Africa to Mexico, the Caribbean and South America.
Marijuana gained a following in the U.S. only relatively recently. During the second half of the 19th century and the beginning of the 20th, cannabis was freely available without a prescription for a wide range of ailments, including migraine and ulcers. Immigrants from Mexico introduced it as a recreational drug to New Orleans and other large cities, where it became popular among jazz musicians. By the 1930s it had fallen into disrepute, and an intense lobbying campaign demonized "reefer madness." In 1937 the U.S. Congress, against the advice of the American Medical Association, passed the Marijuana Tax Act, effectively banning use of the drug by making it expensive and difficult to obtain. Ever since, marijuana has remained one of the most controversial drugs in American society. Despite efforts to change its status, it remains federally classified as a Schedule 1 drug, along with heroin and LSD, considered dangerous and without utility.
Millions of people smoke or ingest marijuana for its intoxicating effects, which are subjective and often described as resembling an alcoholic "high." It is estimated that approximately 30 percent of the U.S. population older than 12 have tried marijuana, but only about 5 percent are current users. Large doses cause hallucinations in some individuals but simply trigger sleep in others. The weed impairs short-term memory and cognition and adversely affects motor coordination, although these setbacks seem to be reversible once the drug has been purged from the body. Smoking marijuana also poses health risks that resemble those of smoking tobacco.
On the other hand, the drug has clear medicinal benefits. Marijuana alleviates pain and anxiety. It can prevent the death of injured neurons. It suppresses vomiting and enhances appetite--useful features for patients suffering the severe weight loss that can result from chemotherapy.
Finding the Responsible Agent
Figuring out how the drug exerts these myriad effects has taken a long time. In 1964, after nearly a century of work by many individuals, Raphael Mechoulam of the Hebrew University in Jerusalem identified delta-9-tetrahydrocannabinol (THC) as the compound that accounts for virtually all the pharmacological activity of marijuana. The next step was to identify the receptor or receptors to which THC was binding.
Receptors are small proteins embedded in the membranes of all cells, including neurons, and when specific molecules bind to them--fitting like one puzzle piece into another--changes in the cell occur. Some receptors have water-filled pores or channels that permit chemical ions to pass into or out of the cell. These kinds of receptors work by changing the relative voltage inside and outside the cell. Other receptors are not channels but are coupled to specialized proteins called G-proteins. These G-protein-coupled receptors represent a large family that set in motion a variety of biochemical signaling cascades within cells, often resulting in changes in ion channels.
In 1988 Allyn C. Howlett and her colleagues at St. Louis University attached a radioactive tag to a chemical derivative of THC and watched where the compound went in rats' brains. They discovered that it attached itself to what came to be called the cannabinoid receptor, also known as CB1. Based on this finding and on work by Miles Herkenham of the National Institutes of Health, Lisa Matsuda, also at the NIH, cloned the CB1 receptor. The importance of CB1 in the action of THC was proved when two researchers working independently--Catherine Ledent of the Free University of Brussels and Andreas Zimmer of the Laboratory of Molecular Neurobiology at the University of Bonn--bred mice that lacked this receptor. Both investigators found that THC had virtually no effect when administered to such a mouse: the compound had nowhere to bind and hence could not trigger any activity. (Another cannabinoid receptor, CB2, was later discovered; it operates only outside the brain and spinal cord and is involved with the immune system.)
As researchers continued to study CB1, they learned that it was one of the most abundant G-protein coupled receptors in the brain. It has its highest densities in the cerebral cortex, hippocampus, hypothalamus, cerebellum, basal ganglia, brain stem, spinal cord and amygdala. This distribution explains marijuana's diverse effects. Its psychoactive power comes from its action in the cerebral cortex. Memory impairment is rooted in the hippocampus, a structure essential for memory formation. The drug causes motor dysfunction by acting on movement control centers of the brain. In the brain stem and spinal cord, it brings about the reduction of pain; the brain stem also controls the vomiting reflex. The hypothalamus is involved in appetite, the amygdala in emotional responses. Marijuana clearly does so much because it acts everywhere.
Over time, details about CB1's neuronal location emerged as well. Elegant studies by Tamás F. Freund of the Institute of Experimental Medicine at the Hungarian Academy of Sciences in Budapest and Kenneth P. Mackie of the University of Washington revealed that the cannabinoid receptor occurred only on certain neurons and in very specific positions on those neurons. It was densely packed on neurons that released GABA (gamma-aminobutyric acid), which is the brain's main inhibitory neurotransmitter (it tells recipient neurons to stop firing). CB1 also sat near the synapse, the contact point between two neurons. This placement suggested that the cannabinoid receptor was somehow involved with signal transmission across GABA-using synapses. But why would the brain's signaling system include a receptor for something produced by a plant?
continued...