EXPLORING WAYS TO ADMINISTER MARIJUANA AS A MEDICINE

The exact location is a secret. But somewhere between London and Brighton a
compound ringed by high fences and razor wire will house the world's only
pot farm primarily devoted to commercial drug development. In June
the British Home Office gave a startup pharmaceutical company a license to
grow 20,000 marijuana plants of varied strains.

Geoffrey W. Guy, chairman of GW Pharmaceuticals, intends to proceed to
clinical trials with a smokeless, whole-plant extract, while also supplying
marijuana to other investigators interested in medical research and
pharmaceutical development.

The 43-year-old entrepreneur-physician wants to capitalize on what he sees
as the unexploited opportunity to legitimize marijuana as medicine.

"Cannabis has been much maligned," Guy says. "There are over 10,000
research articles written on the plant, and there's something well worth
investigating here."

The idea of giving this alternative medicine a place alongside antibiotics
and aspirin in the physician's standard pharmacopoeia is by no means a
new one. Marijuana and its chemical constituents have aroused interest as
a treatment for conditions ranging from the nausea induced by cancer drugs
to the fragility of brain cells harmed by stroke. In the U.S., oral doses
of delta-9-tetrahydrocannabinol (THC)--a synthetic version of the
chemical in marijuana that both relieves nausea and gets a person high--have
been available on the market since 1986.

But the makers of Marinol (the trade name for the THC synthetic) have had
trouble competing with dealers on the street. A swallowed pill takes too
long to relieve nausea. "The maximum levels of THC and the active
metabolites you see after you swallow a capsule occur at anywhere from two
to four hours," says Robert E. Dudley, senior vice president of Unimed
Pharmaceuticals in Buffalo Grove, Ill., Marinol's manufacturer. "That's
contrasted with a marijuana cigarette, where the peak levels might
occur from five to 10 minutes."

Unimed and other companies are in various stages of developing nasal
sprays, sublingual lozenges, vaporizers, rectal suppositories or skin
patches that will deliver THC into the bloodstream quickly. But new
interest in marijuana as pharmaceutical goes beyond just substitutes for
smoking. Guy's motivation for establishing GW borrows a page from the
herbal medicine literature. He hypothesizes that the plant's 400 chemicals,
including dozens of cannabinoids such as THC, may interact with one another
to produce therapeutic effects. A few studies have shown that one
cannabinoid, called cannabidiol, may dampen some of THC's mind-altering
effects. And synthetic THC users sometimes report feeling more anxious than
smokers of the drug, perhaps because of the absence of cannabinoids other
than THC.

GW Pharmaceuticals wants to test whole-plant extracts for a series
of medical conditions. A Dutch company, HortaPharm, will provide seeds to
GW for plants that contain mainly one cannabinoid. Different single
cannabinoid plant extracts can be blended to provide the desired chemical
composition.

Interest in whole-plant medicinal marijuana has even stirred in the
U.S., where research on the drug has been stymied for 20 years. That bias
may be shifting, as witnessed by a 1997 National Institutes of Health
advisory panel that recommended more research on the subject. Robert W.
Gorter, a professor at the University of California at San Francisco, has
received approval from the Food and Drug Administration to perform a
clinical trial on an orally administered whole-plant extract--and he is
also organizing a separate investigation with patients in Germany and the
Netherlands.

"Various cannabinoids in the plant appear to work in a little symphony,"
Gorter observes.

Pushing whole marijuana as medicine is not a task for the fainthearted.

Financing pharmaceutical development for a controlled substance may
not come easy. "I need the right type of people as backers," Guy says. "I
don't want people from Colombia turning up with suitcases full of dollar
bills."

In addition, some scientists observe that evidence for
cannabinoid synergies is relatively slim. "There has never been an effect of
marijuana that has not been reproduced with pure delta-9-THC," says John P.
Morgan, a professor of pharmacology at the City University of New York.
"Herbal medicine advocates think that plants are better because there's a
mix of natural substances. There's not much basis for most of these claims."

Ultimately, advocates of marijuana as natural medicine may find their work
superseded by developments stemming from discoveries of cannabinoid
receptors in the human body--and of molecules that bind to them. Some
research groups are seeking analogues to the binding molecules naturally
present in the body that might provide therapeutic benefits superior to
those of plant-based cannabinoids.

Receptor research is also shedding light on the role played by the
cannabinoids found in marijuana. NIH investigators reported in the
Proceedings of the National Academy of Sciences in early July that THC and
cannabidiol serve as powerful antioxidants. In laboratory rat nerve cells,
the compounds can prevent the toxic effects of excess glutamate, which can
kill brain cells after stroke. (After reading this report, legalization
advocates reveled at the notion that marijuana may actually protect brain
cells.)

To proponents of legalization of the smokable herb, arguments about
alternatives remain academic. "Because patients are receiving full relief
right now from smoking the whole plant, we shouldn't let them suffer while

science plods along trying to come up with synthetic analogues that
may not have the same beneficial effect," says Allen F. St. Pierre,
executive director of the National Organization for the Reform of Marijuana
Laws Foundation.

Some medical users would rather fight than switch from joints or brownies.
Elvy Musikka, a glaucoma patient in Hollywood, Fla., is one of eight people
enrolled in a federal program that supplies the drug for medical reasons.

She maintains that if her legal supply is cut off she will move to a
country where she can grow her own. "I think for the pharmaceutical
companies to think they produce a better product than God is totally
presumptuous," she says. Pharmaceutical makers may find that Musikka's
attitude--shared by thousands--becomes the biggest impediment to successful
drug development.