MEDICAL MARIJUANA poses dilemmas for politicians, but scientists see tremendous therapuetic promise in the drug's derivatives and synthetic forms.
The U.S. Supreme Court's recent decision against Californias 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 Marinola synthetic pill made by Unimed Pharmaceuticalshas 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 doesnt 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 wont let the agonist in." Delta9tetrahydrocannabinol, or THC, one of the main active ingredients in marijuanais an agonist, for instance. Given to an AIDS patient or cancer patient, who may be losing weight dramatically, Felder says, "it stimulates their appetite."

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 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 thingsits 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 Parkinsons disease and Tourettes 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.

Martins 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 patients 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 doesnt 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 researchand the distilled ingredients and application methods that are growing out of itpharmaceutical 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.