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, =46elder 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. Naomi Lubick

Pubdate: Mon, 04 Jun 2001 Source: Scientific American (US) Copyright: 2001 Scientific American, Inc Contact: editors@sciam.com Website: http://www.sciam.com/

Details: http://www.mapinc.org/media/404 Bookmark: http://www.mapinc.org/ocbc.htm (Oakland Cannabis Court Case) Bookmark: http://www.mapinc.org/mmj.htm (Cannabis - Medicinal)

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 ).

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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?"