. .:::::. .::::::::. ...:::::::::.. :::::::::::: ..:::::::::::::::::.. ::::: :::: .::: ::::::: :::. :::::. : :: ::::: :: :::::::. : ::: : :::::::::. ::: :::::::: ::: ::::: ::::: : :::: ::::: oxic :::......:::: hock .:::::::. ::::::::::: ::::::::::: ::::::::: presents The Chemisty of Reefer Madness Source: Omni; August,89 p18 'Mind' By Leah Wallach Keyed by Fetal Juice Toxic File #79 It makes Homo sapiens hungry, horny, drowsy, and glad - or anxious. It dulls pain, inhibits movements, lowers body temeperature, fools time. It sets memory chasing its own tail and turns thought and preceptual processes awry. Why? For decades there were as many theories of how people got high on pot as there were researchers interested in testing the 421 compounds found in marijuana's serrated green leaves. Some scientists thought the weed's active compounds just dissolved into the membranes surrounding brain cells. Others believed the compounds worked through receptors, specialized areas on the membranes that fit lock-and-key style with specific molecules. One prominent neurochemist confessed to three notebooks of experements that had failed to find a neuronal lock for a Cannabis sativa key. No one was able to figure out exactly how marijuana really did work until last year. In the fall of 1988 pharmacology professor Allyn Howlett and her group at St. Louis University Medical School announced that hey had found the receptor for a major cannabinoid molecule. The story of Howlett's discovery began in the Sixties, when Rafael Mechoulam of the Hebrew Univerisity in Jerusalem determined that the main psychoactive compound in extracts of marijuana was a substance called delta-9-tetrhydrocannabinol (THC). Although not especially potent, THC represented a new class of compounds structurally different from those found in other psychoactive drugs. Drug companies were intrigued. "If you look in an old pharmacology text from, say, the Twenties, before the Reefer Madness business," Howlett explains, "extracts of cannabis were about the only compounds that could be used for pain relief and anxiety." Subsequently pharmacologists began synthesizing THC analogs called cannabinoids, where were chemicals structurally and biologically similar to the naturally occuring chemicals but more powerful. In the mid-Seventies Ross Johnson and Larry Melvin worked with synthetic cannabinoids at Pfizer, a Connecticut based pharmaceutical company. They were trying to develop a THC-like analgesic. The problem, Melvin explains was that they couldn't detach the painkilling from pot's psychoactive properties. They developed several compounds 100 times more potent than THC, but the animal (and, in one case, human) subjects were zonked. This meant the drugs could be used only in hospitals, where opiates had already cornered the pankiller market. In the early Eighties Pfizer stopped the research project. The academic community took over and began studying the Pfizer cannabinoids. When a compound locks into its receptor on a cell membrane, it changes the activity of structures in the membrane, which in turn alters the way the cell processes information. Howlett wanted to see if the Pfizer cannabinoids worked the way some other analgesics do: by affecting a molecule called cyclic AMP (cAMP). Cyclic AMP is a "second messenger": it regulates the way the inside of the cell responds to messges recieved at the membrane. Howlett found that the Pfizer cannabinoids--especially the potent Levonantradol--affected cAMP production in cultured mouse neurons bu inhibiting a key enzyme. The more effective the compound inhibited cAMP in the test tube, the more effectively it killed pain in the animals. Howlett's next step was to see if the cannabinoids actually attached to neuronal membranes. She labeled the compounds radioactivety, and by tracking the radioactivity, she was able to show that the cannabinoid molecules bound tightly to the membranes. "The compounds that bound most strongly were the ones most active at the cellular level, and in the animals. And that," she says, "is what really defines a receptor." She also found--potheads might be interested to know--that the cannabinoids did not hurt the cells. After exposure for several hours, however, the cells no longer responded to the drug. That suggests, despite what ganja smokers might say, that it takes increasingly large doses to get the same buzz. Billy Martin, a cannabinoid researcher at the Medical College of Virginia, tested the Pfizer cannabinoids on a variety of animals to see if alterations in cAMP production were related to painkilling power alone or to the panoply of behavioral effects tha make up a THC high. "It looks as though the structure of the compounds might be correlated with other behavioral effects besides analgesia," Martin says carefully. In words of another researcher, "Probably we've seen people at parties who were like these animals: out to lunch." If the investigators could prevent THC effects by stopping up the cell receptor sites, they would be able to prove conclusively that the binding of cannabinoids to cell membranes causes the high. "We need an antagonist," Matrin explaines. (An antagonist is a chemical key that fits into the same receptor lock as the drug but will not trigger the same responce--in this case, getting stoned.) Antagonists could provide a power tool for drug research: By selectively blocking some, but not all, cannabinoid effects, they could help scientists tease apart THC's complex activities. Antagonists and analogs might also have therapeutic value. Scientists might discover more refined versions of the cannabinoid compounds now being used to tread glaucoma and decrease nausea during chemotherapy. The compounds could be used for brain research as well. "It has been noted in people who use marijuana that they can't remember later things they learned while high," says Howlett. "You see something similar in the dementia of aging or the first stages of Alzheimer's." THC analogs, she speculates, might be used as a model for studying what happens in Alzheimer's. And an antagonist might help treat the disease. "We also could learnd more about pain mechanisms and pathways," she continues. "This receptor suggests that opioids are not the only drugs involved in the regulation and processing of the pain response in the central nervous system." Miles Herkenham of the National Institute of Mental Health has used autoradiography--a technique allowing precise location of binding sites--to map the distribution of the Pfizer analogs in the brain. Noting the arrangement of binding sites in areas associated with movement, he wonders if THC analogs and antagonists can relieve symptoms of movement disorders suchs a Parkinson's disease and Huntington's chorea. If THC analogs or antagonists prove to have therapeutic properties, it will be because the mimic or block the action of natural endogenous substances that use these pathways. Howlett's next project is to look for the brain chemical that normally binds to the cannabinoid receptor. She has rulled out all known neurotransmitters. Scientists presume thse receptors did not evolve so that animals could get stoned. "There must be some kind of neuronal pathway in the brain that developed whether there were cannabis plants or not," she says. "We looked at hormones, steroids, glucocorticoids, peptides, and forth nothing else that would bind to the site," notes Howelett, who found the same response in chickens, turtles, frogs, and trout. "Cannabinoid binding sites in their brains were nearly as dense as in later-evolved mamals. We even found some in fruit flies." In rats Howlett found the highest density of cannabinoid receptors in the cortex and hippocampus (areas of the brain asociated with memory, perception, and cognition) and in the cerebellum and striatum (both areas associated with movement). Miles Herkenham found that the pattern of distribution Howlett saw in rats also characterized the human brain. The receptor sites were densest in the hippocampus, cerebral cortex, and areas of the cerebellum. "What really struck me," he says, "was the front-brain loading. It's sort of high-brow receptor." Herkenham was also impressed by the sheer quanity of receptors. "The binding sites are incredibly numerous compared with other neurotransmitter systems," he says, "which suggest they are receptors for an important, ubiquitous transmitter." Unraveling the mystery of this ubiquitous pot transmitter will help us understand how humans and other vertebrates manage the extraordinary juggling act of living. The chemistry of reefer madness will give us another way to look inside the hungry, horny, drowsy, excitable, glad, anxious, musing, giggly, cogitating, perfectly sober brain. (c)opied right from Omni rag-azine..Fetal Juice/Toxic Shock July 1990