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Sticky Business

Much of the cannabinoid system is still a mystery to researchers in the field, largely because the cannabinoid system is a difficult one to study.

Part of the problem is that cannabinoids are lipid molecules—one of a plethora of long-chain fatty acid molecules that are major constitutive components of the brain. Rather than looking for a needle in a haystack, looking for the cannabinoids in the brain is like liking for a particular type of hay in a haystack. Further complicating matters is that cannabinoids have degradation systems that remain uncertain, although TSRI Associate Professor Benjamin Cravatt has made great strides in recent years on elucidating the details of the degradation mechanism modulated by the enzyme fatty acid amide hydrolase (FAAH)—including solving the structure of FAAH last year.

Even if scientists can separate the cannabinoid lipids from the other long-chain fatty acids, the molecules are still hard to work with because of the nature of these substances. "They stick to your tubing, your experimental apparatus," says Schweitzer. "To sort out and work with these molecules is difficult."

For this reason, the field is still relatively new, even though it has grown rapidly in the last few years. It was only a decade ago, says Schweitzer, that the first cannabinoid receptor was discovered. And it was only in the mid-1990s that chemicals that could block these receptors were developed.

Schweitzer himself started in the field by looking at the specific question of how THC works in the brain, but has since expanded his horizons to encompass a few larger questions. One of these is what purpose the endogenous cannabinoid system serves in the brain—especially given the vast number of CB1 receptors there and their concentration in vital parts of the brain, like the hippocampus.

"How do cannabinoids work and what are they there for?" asks Schweitzer. "We still don't know why they are there."

There is no shortage of opinions in the scientific community on this, says Schweitzer. And the implications of this field for politics and drug enforcement makes some of the debates as sticky as the lipidic molecules themselves. But scientists like Schweitzer are slowly gathering the tools and making the analyses needed to begin to unravel the complexities of the endogenous cannabinoid system and the effect that THC has on it.

Hunger and Pain?

One of Schweitzer's main goals is the potential applications that would follow if this endogenous cannabinoid system could be manipulated to achieve a desired effect. "This is of primary importance—the objective of pharmacological research," he says.

When you feel pain, you release natural endocannabinoids, which provide some natural pain relief. For example, the body releases an endogenous cannabinoid called anandamide, a name derived from the Sanskrit word meaning "internal bliss." Recently, Schweitzer, in collaboration with Daniele Piomelli, who is now at the University of California, Irvine, characterized another endogenous cannabinoid found in the brain. This new cannabinoid, called 2-arachidonylglycerol, turned out to be present in much larger amounts than anandamide in the brain.

When the body senses pain, these substances bind to CB1 and nullify pain by blocking the signaling. However, this effect is weak and short-lived as other molecules metabolize the endogenous cannabinoids. These compounds have a half-life of only a few minutes in vivo.

The possible applications for designer chemicals that could inhibit the degradation of endogenous cannabinoids, inhibit their transport, or enhance their formation are tantalizing. If the right chemicals could be made, they might be developed into drugs for a number of clinical conditions—from appetite modulation to safer and more effective painkillers. The market for such compounds would be huge.

The challenge for scientists is to use the cannabinoid system to produce effective, long-lasting relief from pain or viable appetite modulation without the deleterious side effects of marijuana use.


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Schweitzer is interested in the possibility of applying his work to the problems of appetite modulation and pain relief. Photo by Jason Bardi.