RESEARCHERS FIND DRUG HIGH A POTENT FIELD OF INQUIRY

SAN DIEGO - A decade ago, when Daniele Piomelli went to scientific
conferences, he was often the only researcher studying cannabinoids, the
class of chemicals that give marijuana users a high.

His work often drew snickers and jokes - but no more. At the annual Society
for Neuroscience conference last week, scientists here delivered almost 200
papers on the subject.

Why the attention? Many scientists think marijuana-like drugs might be able
to treat a wide range of diseases, far beyond the nausea and chronic pain
typically treated with medical marijuana.

Researchers here presented tantalizing evidence that cannabinoid drugs can
help treat amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease),
Parkinson's disease and obesity. Other researchers are studying whether the
compounds can help victims of stroke and multiple sclerosis.

Although the chemicals work on the same area of the nervous system, the new
drugs are much more refined and targeted than marijuana, with few of its
side effects.

"Cannabinoids have a lot of pharmaceutical potential," said Piomelli, a
neuroscientist at the University of California, Irvine. "A lot of people
are very excited."

Although the federal government opposes the use of medical marijuana, it
generally doesn't restrict cannabinoid research, most of which doesn't
involve the cannabis plant itself. Scientists who use Marinol, a legal but
tightly regulated marijuana-like drug, do need government permission.

Because the cannabinoid system wasn't discovered until the late 1980s -
decades after serotonin, dopamine and other neurotransmitters - researchers
still know relatively little about how it works.

Like all neurotransmitter networks, the cannabinoid system consists of a
series of chemical pathways through the brain and nervous system. Marijuana
produces its effects by activating this pathway, primarily through the
effects of tetrahydrocannabinol, or THC, the drug's main active ingredient.

Over the past decade, researchers have been following these abundant trails
to determine their real purpose. "You don't have them there to get stoned.
So there must be internal reasons," said Andrea Giuffrida, a neuroscientist
at the University of Texas Health Sciences Center in San Antonio.

Researchers have learned that endogenous cannabinoids - internal brain
chemicals that activate the system - play a role in tissue protection,
immunity and inflammation, among other functions. The cannabinoid system
also appears to exert wide influence, modulating the release of dopamine,
serotonin and other neurotransmitters.

Giuffrida and others think cannabinoids can treat degenerative disorders
like Parkinson's disease and ALS.

At the conference, Giuffrida announced that a cannabinoid drug wards off
Parkinson's-like effects in mice.

The disorder, which afflicts more than 1 million Americans, destroys
neurons in a key part of the brain, causing patients to lose control over
movement.

Giuffrida, with colleagues David Price and James Roberts, injected mice
with a chemical called MPTP, which mimics Parkinson's damage. When some of
the animals subsequently received a drug that blocks cannabinoid receptors,
their nerve cells suffered far less damage than did the cells of the other
mice. This was the first demonstration that a cannabinoid drug can have
this effect.

While he isn't sure how the anti-cannabinoid compound works, Giuffrida
suspects it protects neurons by reducing inflammation, a key component in
Parkinson's.

Cannabinoids might also slow down ALS, which destroys neurons that control
muscles until victims become paralyzed, unable to breathe on their own.

ALS Experiments

Neuroscientist Mary Abood first became interested in cannabinoids after
hearing about ALS patients who got some relief from smoking marijuana. So
she began animal experiments at the California Pacific Medical Center in
San Francisco.

In her study, mice with a variant of ALS were given a combination of THC
and cannabidiol, another compound found in marijuana. Both substances are
cannabinoid agonists, chemicals that activate the cannabinoid system.

Abood measured the course of the ailment by testing how long the mice could
stand on a slowly rotating rod.

The treatment delayed disease progression by more than seven days and
extended survival by six days. In human terms, this would amount to about
three years. That's a significant improvement over the only existing ALS
drug, riluzole, which extends life by two months. "I was very excited when
I got my initial results," Abood said.

Also at the conference, researchers at the Institute of Neurology in London
announced results that corroborated her findings. Cannabinoids have also
helped some human ALS patients in one small trial. and Abood is trying to
get funding for a larger one.

If cannabinoids can shield human neurons from harm, researchers say, they
might prove useful against other neurological diseases, including mental
illness. Scientists are looking at whether cannabinoids can treat multiple
sclerosis, epilepsy and Huntington's disease, while Giuffrida is beginning
a study of their effect on schizophrenia.

Some schizophrenics say marijuana lessens their psychotic symptoms, and
studies have shown that schizophrenic patients have abnormal brain levels
of cannabinoids.

Marijuana-like drugs might also help treat stroke. Soon after a stroke, the
injured brain region is flooded with a neurotransmitter called glutamate,
which at high levels is lethal to neurons.

Cannabinoids seem to protect against this destruction, and Israeli
scientists are studying whether increasing cannabinoid levels soon after
stroke can minimize harm.

Advocates of medical marijuana have long argued that the drug can be useful
for treating many conditions, particularly chronic pain, nausea and
glaucoma (in the latter, marijuana works by temporarily decreasing pressure
around the eye).

Although they don't dispute this view, most researchers think there are
better, more precise ways to stimulate the cannabinoid system. They believe
marijuana has too many negatives to be a truly effective drug, with side
effects that include memory problems, decreased immunity and possibly
addiction. (Some researchers dispute this.)

'A Very Dirty Drug'

Marijuana has another drawback. From a scientific standpoint, Giuffrida
says, it's "a very dirty drug."

It contains more than 300 compounds, 60 of which affect the cannabinoid
system. Scientists don't understand what most of these substances do or how
they work together. This complexity makes it hard for researchers to
pinpoint marijuana's effects.

One cannabinoid, Marinol, is available legally. The compound, which
contains THC in a pill form, is usually prescribed for nausea and for
appetite loss among AIDS patients.

But Marinol has the same psychoactive effects as marijuana. So the key,
Piomelli says, is "getting the effects without the side effects."

To that end, Piomelli has developed a compound called URB597, which doesn't
flood the body with cannabinoids, as Marinol and marijuana do. Instead, it
slows the breakdown of the cannabinoids in the system. He thinks the drug
may help treat pain, anxiety and even depression without making patients
stoned and forgetful. He and others are testing it on animals.

Another cannabinoid compound, Rimonabant, will likely be available much
sooner, as a diet drug. It lowers cannabinoid levels and seems to reduce
appetite - the opposite effect of the intense "munchies" that marijuana
users experience.

Early results from human clinical trials indicate that it helps patients
lose weight, although some subjects report side effects that include
diarrhea and depression. The drug might also be able to reduce cravings for
alcohol and nicotine, researchers say.

For Piomelli, this explosion of research has an added bonus. A few years
ago, when he told people what he did for a living, they'd often giggle and
ask him if getting high was part of his job. These days, he doesn't hear as
many snickers.

"The work is so exciting that it is eliminating the stigma of being
associated with marijuana," he says. "People realize that it's not just
'Let's take some marijuana and give it to people.'"