RESEARCHERS BUZZING ABOUT MARIJUANA-DERIVED MEDICINES

Cannabinoids May Help Against Many Diseases

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 delivered
almost 200 papers on the subject.

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

Researchers presented tantalizing evidence that cannabinoid drugs can
help treat amyotrophic lateral sclerosis, known as 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 UC 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 believe cannabinoids can treat degenerative
disorders such as 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 much 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 is not 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.

Neuroscientist Mary Abood 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 believe 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.

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 probably 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.

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 said. "People realize that it's not
just 'Let's take some marijuana and give it to people.' "