Marijuana is a great example of the differences between science, policy and rational thought.

California has legalized medical marijuana use for certain indications when prescribed by a physician, and since 1996, nine other states have done the same, according to data from the National Organization for the Reform of Marijuana Laws.

Officially, it is classified as a Schedule 1 drug, meaning that it has a high potential for abuse, has no accepted medical use in the United States, and is considered unsafe even when used under medical supervision. Beyond the fact that is is approved in some areas, that classification of Schedule 1 is logically difficult to reconcile with the fact that synthetic tetrahydrocannabinol, or THC, the psychoactive ingredient in marijuana, has been approved as Marinol in the U.S. since 1985 for nausea in chemotherapy patients, and since 1992 as an appetite stimulant for AIDS patients.

Why, then, all the scrutiny on a substance that has potential curative properties?

"This is an old conundrum," said Daniele Piomelli, professor of pharmacology at the University of California at Irvine, whose research focuses on cannabinoids, adding that the classification seems "to fly in the face" of a body of data that suggest THC has medicinal uses.

It would seem that in the eyes of the federal government, testing cannabinoids is permissible, but approvals are another matter. A Supreme Court ruling against marijuana's medical value does support research, saying that the Controlled Substances Act that led to the drug's Schedule 1 classification "reflects a determination that marijuana has no medical benefits worthy of an exception outside the confines of a government-approved research project." Federal drug policy explanations from the White House, found on its website, also acknowledge that THC "can be useful for treating some medical problems."

Pick Your Battles

Piomelli told BioWorld Today that the National Institute on Drug Abuse, part of the National Institutes of Health, is an enthusiastic backer of his basic preclinical research and that of others in the same space. But beyond that, he said, the apparent contradiction is not worth a fight.

"Trying to change federal regulations is not useful," noted Piomelli, adding that he doesn't expect research to change regulations, regardless of the leanings of particular administrations - the subject is too much of a political hot potato. "What I think is probably more useful is trying to understand how to use the knowledge that we are acquiring on the potential therapeutic uses of THC to make compounds and medicines that are not liable to any form of addiction."

That is not to say that the classification of cannabinoids as potentially dangerous is unjustified. In fact, a paper published recently in BMC Psychiatry reported on two cases of acute cannabis-induced psychosis in subjects during a clinical experiment on effects of THC. Notably, both subjects experienced their reactions with blood concentrations of lower than 10 ng/ml - the usual threshold concentration for psychoactive effects when smoking pot. One subject's blood concentration was less than half that. The researchers hypothesized that administering THC orally rather than through the lung might lead to different metabolites and thus, stronger psychoactive effects.

French firm Sanofi-Aventis has completed Phase III trials for Acomplia (rimonabant) for obesity and smoking cessation and expects to file for marketing approval with the FDA during the second quarter of 2005. Rimonabant is thought to regulate appetite by blocking CB1 receptors in the brain. Research in the May 1, 2005, issue of the Journal of Clinical Investigation shows that in the liver, the same receptors regulate fat metabolism. The authors, from Virginia Commonwealth University in Richmond and the Scripps Institute in La Jolla, Calif., said "targeting both of these pathways with CB1 antagonists could promote sustained weight loss and favorable serum lipid profiles in obese patients."

Going After Cardiovascular Disease Directly

Cardiovascular disease is a well-known consequence of obesity, and cannabinoids also might be a useful target to affect cardiovascular disease directly. Scientists from the University Hospital in Geneva and the University of Bonn in Germany reported in the April 7, 2005, issue of Nature that, as the title of the paper succinctly states, "Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice."

In the Nature study, scientists used Marinol to treat ApoE knockout mice, a mouse strain susceptible to atherosclerosis. After initial experiments to determine an effective dose, the scientists first fattened up two groups of mice for five weeks, and then added a daily dose of THC to their diet for the next six weeks, while continuing on the high-fat regimen. Five weeks of mice gorging themselves was sufficient to induce atherosclerotic lesions; after 11 weeks, those lesions had grown significantly worse in control animals than in those who had received Marinol.

To investigate the mechanisms of the protective effect, the researchers next investigated the effects of Marinol on specific immune system cell types. Staining studies showed that Marinol exerted its protective effects by altering the balance between pro-and anti-inflammatory T cells in the atherosclerotic lesions; THC specifically binds to IfN-gamma-secreting T cells and inhibits their response. In in vitro experiments, Marinol also inhibited macrophage migration, which also would be expected to reduce proinflammatory inflammation processes in atherosclerotic lesions. The effects of THC could be blocked by a cannabinoid receptor antagonist, showing that they were not due to unspecific effects of Marinol on other receptors.

That research is part of an increasing interest in the field. And while the perception might be that the government is stacked against it, that's not necessarily so.

"The National Institutes of Health is very interested in seeing what we researchers can do to use the knowledge of the cannabinoid system to make better medications," Piomelli said. "I think there is a perception that the federal government causes a lot of trouble to researchers working in this area, and I think that perception is probably a little overblown."