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Meredith Wadman
Fortune Magazine, US

Monday 17 Nov 2003
(From the Nov. 24, 2003 Issue)

The brain's cannabinoid receptor is the target of a rush (ha!) to develop
new drugs.

If you're among those of us who did inhale, you'll recall one of the weed's
enjoyable side effects: intense attacks of the munchies that sent you
scurrying for baked beans and Moon Pies faster than Pooh after honey. So
you may appreciate this tasty irony: Drug companies are racing to develop
pills that plug into the same brain-signaling system that once had boomers
flying high - this time to help them lose weight.

Experimental drugs that block the brain receptor activated by
marijuana - called the cannabinoid receptor - are showing clear promise in
fighting obesity. And that's not the only vice that may soon be treatable
with this new breed of mind medicine. Predilections for Marlboros and
martinis are also targets of a new drug now in human trials and nearing the
clinic, with imitators hot on its tail.

Farther from the pharmacist's counter but still firing up a lot of interest
are experimental compounds that work not by blocking cannabinoid receptors
but by activating them. These are squelching strokes, allaying anxiety, and
easing pain in lab animals. There's even a suggestion that drugs that
stimulate cannabinoid receptors in sperm may one day yield a contraceptive
for men. If only they'd remember to take it! (All is not lost on this
score - the cannabinoid system is important in the function of memory as well.)

"The cannabinoid area is getting ready for prime time," says Daniele
Piomelli, a leading researcher at the University of California at Irvine.
"What makes it particularly promising is that there are a lot of companies
working on these classes of compounds."

It's hard to overstate just how important - and rare - it is to identify an
entirely new class of brain receptors, the neurotransmitters that act on
them, and the molecules that ferry those neurotransmitters or break them
down. Consider the pharmaceutical and cultural revolution launched with the
discovery of the transporter for serotonin, which led to the development of
Prozac, Zoloft, and other antidepressants. The body's home-grown
cannabinoid neurotransmitters and their receptors - discovered only in the
past 13 years - could give rise to a whole new generation of blockbusters.
"It's one of the hottest areas in neuroscience," says George Kunos,
scientific director at the National Institute on Alcohol Abuse and Alcoholism.

The big players now in the lab with cannabinoid-related experimental drugs
include Merck, Pfizer, and Bristol-Myers Squibb. But the undisputed leader
is the French company Sanofi-Synthelabo, which is in late-stage human
trials for its drug Rimonabant. Sanofi's pill is helping fat people slim
down and quit smoking at the same time.

Rimonabant works by blocking CB1, the brain receptor that marijuana's
active ingredient plugs into. It turns out that nerve cells in the brain
make their own neurotransmitters that plug in here too, called endogenous
cannabinoids. When we enjoy steaks, stogies, or Scotch, these chemical
messengers are pumped out and bind to CB1 receptors in a key "reward" area
of the brain. This sets free a different neurotransmitter: dopamine, the
pleasure queen. So by blocking endogenous cannabinoids from docking at CB1,
Rimonabant snuffs that dopamine buzz and takes the fun out of our worst
habits.

In an early round of the Sanofi trials, which wrap up late next year, obese
people on the highest trial dose of Rimonabant lost an average of ten
pounds in just under four months. Twenty percent of smokers taking the drug
didn't light up during a ten-week trial and lost 2.6 pounds in the bargain.
Trials of Rimonabant in alcoholics are in earlier stages, but in lab mice
with drinking problems its effectiveness is clear.

Sanofi scientists in the late 1980s applied a logic that now seems obvious:
If marijuana brings on the munchies, why not make a molecule that blocks
its action, on the theory that it will fight obesity? Scientists had long
been operating on the faulty theory that the brain didn't have specific
receptors for marijuana's active ingredient. They didn't figure out until
1988 that those receptors existed. CB1 was identified in 1990. All of a
sudden, the cannabinoid system was the hot new kid on the brain-transmitter
block. And Big Pharma, normally shy about reefer-related research, snaps to
attention when the subject is diet pills.

Ultimately, the cannabinoid system could yield therapies that go well
beyond helping people shrink their beer bellies and pitch the Pall Malls.
Compounds that activate cannabinoid receptors are also presenting exciting
possibilities. For instance, it's well established in animals that drugs
that stimulate cannabinoid receptors can limit brain damage in trauma and
stroke. Other promising applications seem to emerge by the month.

Of course, man-made drugs that turn on cannabinoid receptors are bound to
freak out the drug police. So scientists are trying to develop compounds
that fight disease without giving users the giggles. Scientists at the
University of Arizona and the University of Connecticut have used an
experimental drug to increase pain tolerance in rats and mice with
nerve-injured paws. The drug binds to a class of cannabinoid receptors that
occur only outside the brain, meaning that the furry guys get pain relief
without getting high. The applications aren't trivial: Neuropathic pain
from nerve injury affects millions of Americans and doesn't respond well to
existing painkillers. AlexiPharma, a Connecticut startup, is hoping to move
the drug into human trials within a year.

Pain sufferers have been toking up for as long as hemp has been used for
rope. Similarly, the calming effects of low-dose ganja are now being
harnessed - without the high - in experimental drugs that boost levels of one
of the brain's key cannabinoid neurotransmitters, damping down anxiety in
lab rats. That's what Daniele Piomelli is working on at UC-Irvine.
"Rimonabant is the beginning of a chapter, not the end of it," he says. And
he's not just blowing smoke.
From the Nov. 24, 2003 Issue