HEALING HAZE?

As Politicians Debate The Potential Merits Of Medical Marijuana,
Scientists Search For New Ways To Deliver This Old Drug

Photo caption: MEDICAL MARIJUANA poses dilemmas for politicians, but
scientists see tremendous therapeutic promise in the drug's
derivatives and synthetic forms.

Photo caption: NATURAL VERSUS SYNTHETIC. THC (top) is one of
marijuana's most active components. But CP55, 940 (bottom), a
synthetic, is far more potent because it is designed to fit tightly
into the receptor, allowing it to stay active longer.

The U.S. Supreme Court's recent decision against California's
cannabis clubs has revived arguments over the legal use of marijuana
for medicinal purposes. But no matter what the politics, researchers
are continuing to develop synthetics of the drug that can be taken as
a pill or absorbed through a patch. For the past 15 years Marinol - a
synthetic pill made by Unimed Pharmaceuticals - has been the only
available (and legal) alternative to marijuana. But soon Marinol,
which has received mixed reviews, will not be alone on the shelf.

In fact, humans have smoked marijuana for thousands of years; the
plant was given as medicine in the United States until the early
1900s and did not become a controlled substance until 1934. Marijuana
remains a Schedule 1 substance today along with the likes of heroin,
although Marinol was recently "declassified" to a Schedule 3 drug,
which has looser prescription requirements.

Scientists in both academia and the pharmaceutical industry have
tested marijuana derivatives and synthetic forms of the herb for
potentially helpful chemical effects since the 1970s. But the idea
that drugs based on marijuana could benefit people gained real
support only recently. In 1990 Lisa Matsuda cloned CB1, the first
cannabinoid receptor discovered in rats, and Shawn Munro cloned a
second receptor (CB2 in humans) in 1993. From these studies,
scientists came to discover that mammals have their own built-in
cannabinoid molecules (endogenous or endo-cannabinoids).

Indeed, our bodies use endo-cannabinoids in much the same way as they
use opioids in the central nervous system: as synapse agonists and
antagonists. Christian Felder, who once worked with Matsuda at the
National Institutes of Health and now works for Eli Lilly, describes
a synapse as a gap in a line of connections in the brain. He likens
the neurotransmitters released across the gap to bridges. The gaps
help to regulate signaling in the brain, and the bridges are the
"connection across a synapse [that] is the release key that fits into
a very specific lock to initiate the next step."

An agonist is a key that fits in a lock and allows it to open. In
contrast, an antagonist will fit into the lock but doesn't open it.
"It blocks that binding site," Felder explains. "The beauty of that
system is that you create an antagonist and that will sit there like
a block; it won't let the agonist in." Delta9 - tetrahydrocannabinol,
or THC, one of the main active ingredients in marijuana - is an
agonist, for instance. Given to an AIDS patient or cancer patient,
who may be losing weight dramatically, Felder says, "it stimulates
their appetite."

The main difference between endogenous cannabinoids and opioids,
Felder explains, is that cannabinoids are part of the fat family,
which also distinguishes them from other neurotransmitters. As fats
they cannot be stored, like other neurotransmitters, in packages
called vesicles; they need "middlemen" to relay messages from one
cell to another. So far, about half a dozen endogenous cannabinoids
have been identified, but these molecules are not as useful to drug
developers as the rigidly structured lipophilic (or fat-loving) forms
in marijuana. The plant itself contains some 400 cannabinoids, each
of which may have some therapeutic potential. How to use them in a
way that allows the body to reap the greatest benefit, however, is up
for debate.

"Marijuana does 100 different things - it's good for everything,"
says Billy R. Martin, chair of the department of pharmacology and
toxicology at the Virginia Commonwealth University. "You want an
agent that has some selectivity." Cannabis has been found to be
helpful in controlling nausea or vomiting ("emesis"), in pain and
anxiety relief and as an eating stimulant. Research suggests that
cannabinoids can control some movement disorders, such as Parkinson's
disease and Tourette's syndrome, and the presence of a CB1 receptor
in the eye may explain how marijuana eases glaucoma and relieves
intraocular pressure (IOP). There is even some evidence that CB1
receptors play a role in some forms of hypertension, and a recent
report suggests that cannabinoids actually protect neural processes
during brain trauma.

With so many different uses, marijuana looks like manna from heaven
to most pharmaceutical companies, who stand to gain by selling it in
as many forms as possible. Nevertheless, they must first isolate the
beneficial aspects of cannabis and find ways to avoid its side
effects. In fact, the "high" that so many recreational users of
marijuana seek is considered such an adverse effect, especially if it
results in dysphoria. Patients taking drugs for therapeutic reasons
don't normally expect potent psychotropic reactions.

It won't be easy to find the most useful and efficient ways of
delivering marijuana derivatives. Synthetics in pill form such as
Marinol have not been entirely popular. So GW Pharmaceuticals in
Britain has developed a spray applied under the tongue. The product
has now entered Phase Three of the British trials procedure. GW
Pharmaceuticals grows its own marijuana plants in highly controlled
greenhouse environments and clones the plants for different
potencies. Eventually they intend to determine the best combinations
of certain cannabinoids to treat various diseases.

Martin's lab is working on an aerosolized delivery method, much like
an asthma inhaler. "With smoke, the biggest issue is that you are
delivering a mixture of a large number of substances," Martin says.
"With a spray, you are delivering two to three compounds in a
matrix." The advantage with smoke, he continues, is that it delivers
much larger particle sizes of a desired substance than an inhaler
does. "The onset of action and the duration of action," he adds,
"should be comparable as far as the patient's concerned."

With funding from the American Cancer Society, Audra Stinchcomb, a
pharmacologist at the University of Kentucky, is working on
skin-patch delivery systems using about a dozen different synthetic
cannabinoids. "Some patches can actually be left on for a week, so a
patient doesn't need to remember to take their drugs," she says, "and
they get a steady level of medicine for a week." Stinchcomb, who has
yet to test the patches on people, estimates that she will publish
the results next year. In her own trials, she now administers the
test patches to surgical waste skin.

With all of this new research - and the distilled ingredients and
application methods that are growing out of it - pharmaceutical
companies are bound to get involved, if they're not already. But will
the final product be as good as the real thing? Donald Abrams of the
University of California at San Francisco finds the new research
exciting, but he argues that marijuana is a natural drug and,
according to Chinese herbology, should be used as a whole herb to
receive its complete benefits - "the yin and yang, so to speak." At
any rate, it may take another 10 to 15 years before we learn whether
synthetic cannabinoids will fulfill their promise. And that's a long
time to wait for patrons of the California cannabis clubs. =F3Naomi
Lubick

RELATED LINKS:

Herb Remedy (http://www.sciam.com/1998/0998issue/0998scicit1.html)

Center for Medicinal Cannabis Research (http://www.cmcr.ucsd.edu/

FURTHER INFORMATION:

Science of Marijuana. Les Iverson. Oxford University Press, 2000.

Cannabinoid Receptors and Their Endogenous Agonists. Christian Felder
and Michelle Glass in Annual Review of Pharmacology and Toxicology,
Vol. 38, pages 179-200; 1998.

The Endocannabinoid Nervous System: Unique Opportunities for
Therapeutic Intervention. Amy C. Porter and Christian C. Felder in
PharmTox. 2001 (in press).

The Difficulties of a Marijuana Trial

Donald Abrams's struggle to obtain funding for a human medical
marijuana study at the University of California at San Francisco
became a personal quest. "It's a self-fulfilling prophecy," Abrams
says of the lack of such research. "Because there are so many
regulatory hurdles to overcome, people throw their hands up in the
air." Abrams, however, did not give up and the results of his first
study will be released this summer.

Recent California legislation establishing the Center for Medicinal
Cannabis Research (CMCR) at the University of California at San Diego
should make the process somewhat easier. Smoking trials are necessary
in order to reveal the benefits and detractions of using the
whole-herb approach, CMCR director Igor Grant asserts. The absorption
of cannabis, he notes, "is not very predictable from the
gastrointestinal tract." Some patients find that onset of the effects
takes hours. "Uncertainty reported by the patients," Grant says, "is
(a) if they'll get an effect at all, and (b) when they'll get it."

The CMCR is currently awaiting approval from the DEA for its first
round of grants to fund four human trials of smoked marijuana. In
each of these trials, Grant explains, "an investigator will teach
specific smoking procedures in an effort to standardize absorption
and the amount of the drug." Placebo cigarettes will serve to make
certain studies double blind. The DEA decision is expected sometime
in June.

The second round of CMCR grants, which will be released in July, will
probably fund an animal model of pain. Other future trials might
include work with GW Pharmaceuticals, a British company that is
working on oral doses that mix cannabinol and THC, the most active
components of marijuana. With these trials, Grant remarks, the
researchers hope to address among other things whether the mix of the
two cannibinoids is important, and whether they augment or dampen
each other's effects.

Abrams is pleased with the CMCR and the legitimacy it may give to
human trials of medical marijuana. "If it's there and people are
using it," he muses, "why shouldn't we investigate it further?"