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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