167 lines
10 KiB
Plaintext
167 lines
10 KiB
Plaintext
|
|
.
|
|
.:::::. .::::::::.
|
|
...:::::::::.. ::::::::::::
|
|
..:::::::::::::::::.. ::::: ::::
|
|
.::: ::::::: :::. :::::. :
|
|
:: ::::: :: :::::::.
|
|
: ::: : :::::::::.
|
|
::: ::::::::
|
|
::: :::::
|
|
::::: : ::::
|
|
::::: 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
|
|
|
|
|