Cannabis: the brain's other supplier.
	By Rosie Mestel
New Scientist 31 July 1993
Reproduced without permission

Three years ago, Israeli archaeologists stumbled upon a 1600-year-old
tragedy: the remains of a narrow-hipped teenage girl with the skeleton
of a full-term fetus still cradled in her abdomen.  With her were grey
ashes that contained traces of tetra-hydrocannabinol, the active
ingredient of marijuana.  Could it be that the midwife had
administered the plant in a last-ditch effort to bring on labour or to
ease her pain?

Today, in nearby Jerusalem, another chemical is in the news -- this
one extracted not from ancient ashes but from fresh, pulverised pig
brain.  It is anadamide, a newly christened chemical that might do
naturally in our heads what marijuana does when we choose to smoke it.
Anandamide's discovery, along with that of the molecule it binds to in
the brain, has marijuana researchers buzzing with the best high they
have had in years.  The findings provide new hope for therapies that
draw on the weed's long list of anecdotal medical uses: as a
painkiller, appetite stimulant or nausea suppressant, to name a few.
They also throw open windows onto the mysterious workings of our
brains.

[History of marijuana research and use]

More recently came other exciting finds: in 1988, Allyn Howlett of St
Louis University Medical School discovered a specific protein receptor
for THC in mouse nerve cells -- a protein that only THC and its
relatives dock onto.  Two years later, Tom Bonner's group at the
National Institute of Mental Health pinpointed the DNA that encodes
the same receptor in rats.  It is now known that humans have the
receptor, too.

Finding a cannabinoid receptor implies that THC -- unlike alcohol --
has a quite precise modus operandi that taps into a specific brain
function.  Presumably the drug binds to nerves that have the receptor,
and the nerves respond in turn by altering their behaviour.  The
classic effects of marijuana smoking are the consequences: changes in
mood, memory, appetite, movement and perception, including pain.
Researchers think THC affects so many mental processes because
receptors are found in many brain regions, especially in those that
perform tasks known to be disturbed during THC intoxication: in the
banana-shaped hippocampus, crucial for proper memory; in the crumpled
cerebral cortex, home of higher thinking; and in the primitive basal
ganglion, controller of movement.

Once a specially tailored receptor was found, the next step was simple
 - in theory, anyway.  "The receptor had to be there for a purpose -
presumably it didn't evolve so that people could smoke cannabis and
get high," says Roger Pertwee, a pharmacologist at Aberdeen
University.  Instead, there had to be a natural chemical inside of us
that fitted onto the receptor and sent some biochemical signal
cascading through the nerve cell to do who knows what.  But plucking
that one chemical out of a brain stuffed with millions of others was
never going to be easy.

Several laboratories set to work on the problem and, fittingly,
Mechoulam's was the first to come up with an answer, in the form of
a greasy, hairpin-shaped chemical.  The researchers dubbed it
anandamide, from "ananda", the Sanskrit word for bliss.  "The guy
discovers the active ingredient of marijuana back in the 1960s, and
now, almost 30 years later to the day, he discovers anandamide," says
Paul Consroe, a neuropharmacologist at the University of Arizona.
"Isn't that great?"

Mechoulam's strategy was to chase after chemicals that, like THC, are
soluble in fat.  By teasing these substances away from those that are
water soluble, his group extracted a substance from pig brain that did
indeed bind to the cannabinoid receptor.  But did it act like THC? To
find out they sent their specimen to Pertwee who had devised a
sensitive test for cannabinoids that involved monitoring a substance's
ability to stop muscle-twitching in mouse tissue, when dropped on
certain nerves.  "When it arrived, there was so little of it in the
phial I couldn't even see it," Pertwee recalls.  "We didn't know what
it was - just that it was a greasy substance."  But the tests went
well: anandamide depressed the twitch just like THC, and last December
the researchers published their results in "Science".

The mouse result gave Mechoulam and his group the encouragement they
needed to extract more anandamide from pig brains and then analyse
and synthesis the chemical in the lab.  They also wanted more
evidence that anadamide docked specifically onto the cannabinoid
receptor and acted like THC, which has a very different molecular
structure.  And so, with Zvi Vogel and colleagues at the Weizmann
Institute near Tel Aviv, they came up with a plan.  They would add
the DNA encoding the cannabinoid receptor to hamster or monkey cells
growing in dishes.  The cells equipped with this DNA would then
produce masses of receptor, which would sit in the cell membrane
ready and available for any chemical "key" that should happen along.
Vogel's researchers would add anandamide to the cells and watch what
happened.

The results, published in July's issue of the "Journal of
Neurochemistry", were clear: anandamide acted as a key, and a
precise one at that, sticking only to the cells containing the
receptor, and not to others.  What's more, when anandamide stuck to
the cells, it triggered biochemical changes similar to those
associated with THC and related chemicals.  Not only did anandamide
fit the same lock as THC, but it appeared to open similar doors in
the brain.

More tests followed in a number of laboratories, and those researchers
found that in every way that has been tested so far, anandamide acts
very much like THC.  But why would we want such a mind-altering
substance in our brains?

Studies on another class of drugs provide a useful parallel.
Opiates such as morphine and heroin act upon the body's nervous
system to cause euphoria and block pain.  In 1973, natural opioids,
which behave in the same way as opiates, but have a different
structure, were pulled out of the body.  It appears that when the
body is under serious assault, nerve cells spit out these opioids,
which promptly bind to other nerve cells to stop pain signals dead in
their tracks.  At the same time, they fasten onto sites in the brain
to induce a feeling of wellbeing.

Anandamide, like the natural opioids, will probably have its own
specific set of jobs to perform in the brain and body.  The effects
of THC give a rough guide to what these might be: involvement in
mood, memory and pain are obvious examples.

But what would the brain be like without anandamide? Researchers
intend to find out.  Bonner is gearing up to produce a genetically
engineered mouse that has no cannabinoid receptors: no receptors, no
anandamide function.  Others want to tinker with anandamide to make a
version that binds to the receptor but doesn't trigger any change in
the nerve's behaviour.  Added to a mouse, it would stop the body's
real, internal anandamide from doing its job.  Researchers are also
excited by anandamide's possible role in mental and neurological
disease. There are also other questions to be asked.  If anandamide,
like THC, hampers memory, could a drug with the opposite effects - a
"memory pill" - be made?  "It's all speculation for now," says Steven
Childers, a pharmacologist at Bowman Gray School of Medicine, North
Carolina, "but we like to think about these things."

It will take more time before anandamide is firmly established as the
bona fide partner to the cannabinoid receptor.  Meanwhile, Mechoulam's
lab has two other anandamide-like chemicals waiting in the wings.  And
in the US, Howlett and Childers both have chemicals of an entirely
different kind that bind to the receptor: they are water soluble, not
fat soluble.  The importance of each remains to be seen.

Whatever anandamide turns out to be, it provides pharmacologists with
a fresh plan of attack in their hunt for drugs that act like the
cannabinoids.  Such drugs could be valuable to help keep at bay the
nausea of cancer chemotherapy; to stimulate appetite in AIDS patients;
to dampen tremors in neurological disorders; to reduce eye pressure in
patients with glaucoma; and to dull pain in those for whom other
painkillers do not work.

Cannabinoids can do at least some of these things, with one small
drawback: they also make the recipient high.  The holy grail of
cannabinoid therapeutics has been to separate what causes the high
from the source of the desired effects, by chemical tinkering with THC
or its relations - shortening a side group on one part of the
molecule, lengthening a carbon chain in another - in the hope that
the "undesirable" effects will be lost in the reshuffle.  Despite the
drug's dubious reputation, several US pharmaceuticals spent several
years trying to make this work, but without success.  Nor did they
reach another equally sought after goal: an antagonist that will block
the effects of THC and similar substances when taken.

Until marijuana researchers succeed in doing something along these
lines, it is unlikely that drugs companies will pay much attention.
"There is a real stigma with working with drugs of abuse," says Billy
Martin, a pharmacologist at the Medical College of Virginia. "If drugs
companies had three choices of classes of drugs to work on and one was
a drug of abuse, they're just not going to work on the drug of abuse."
This view is shared by Larry Melvin, who worked on the Pfizer
pharmaceuticals company's now defunct cannabinoid therapeutics
programme.  "What will ultimately legitimise the field in a big way is
if researchers can come up with a really good therapeutic ability.
Then you'll see the companies turn around."

But Gabriel Nahas, an anaesthetist from Columbia University in New
York, who has spoken out against marijuana use for many years,
maintains that THC's effects on the brain are too general and too
toxic for this route ever to work.  The discovery of anandamide and
its receptor have not changed his mind.  "The brain is a computer," he
says.  "To put THC in the brain is akin to putting a bug in the
computer.  I'm sticking to my guns about its harmful effects - not
only to man but to society."

Only time will reveal the value of anandamide and its receptor to drug
therapy.  But the importance of these discoveries to brain research is
not in doubt.  "We're no longer just dealing with the pharmacology of
a recreational drug," says Pertwee.  "We're dealing with the
physiology of a newly discovered system in the brain.  And that's an
enormously bigger field."
