This is your brain on marijuana

In recent years, researchers have discovered that the body makes its own marijuana-like molecules

05/28/2001

By DIANA STEELE / Special Contributor to The Dallas Morning News

Medical marijuana proponents may have suffered a setback from the Supreme Court this month, but scientists continue to make progress in understanding the brain system responsible for marijuana's effects on the body.

New research shows that the brain's own marijuana-like molecules might let brain cells talk back to each other. This may be important for forming new memories.

Someone under the influence of marijuana might have trouble remembering things because marijuana's active ingredient, THC, swamps the natural system. Marijuana's other physiological effects – including relieving pain, increasing appetite and interfering with movement – may occur because the brain's related chemicals have some role in regulating all of these functions.

A better understanding of how this natural system works could help scientists develop drugs that harness the medically beneficial effects of marijuana.

"What you'd want is a designer drug that could give you all the benefits of marijuana, but not all of its side effects," says Rachel Wilson, a graduate student at the University of California, San Francisco.

Just 13 years ago, scientists discovered that throughout the brain and central nervous system, there are receptors, or docking stations, that allow THC to stick to brain cells. Four years later, researchers found that the body makes its own marijuana-like molecules, called cannabinoids. There are two known so far.

These molecules act as neurotransmitters, sending messages throughout the brain and central nervous system. The question is, what messages?

New research helps unravel part of the mystery. Ms. Wilson's work shows how the brain's cannabinoids may play a key role in memory. Other new research helps explain why marijuana gives pot smokers the "munchies"; this work may lead to better drugs for appetite suppression.

Ms. Wilson studied neurons in the part of the brain called the hippocampus, the area thought to be responsible for memory. People who have damage to the hippocampus lack the ability to form new memories (like the main character in the movie Memento).

What Ms. Wilson and her adviser, Roger Nicoll, found is that cannabinoids in the hippocampus seem to allow neurons to talk back to each other. Communication between neurons in the brain had long been thought to be one-way. But two-way communication means that the connections between neurons can be strengthened or weakened based on "talking" back and forth – with the cannabinoids as the signal that talks back.

This "is what everyone in neurobiology has been looking for for so long," says Scripps Research Institute biochemist Benjamin Cravatt. This back talk "has a feel of memory to it. ... One neuron tells another neuron ... 'This is what I'm telling you,' and that neuron talks back to it."

The research by the San Francisco scientists was published this spring in the journal Nature, at the same time two teams working independently in Japan and Cambridge, Mass., published complementary findings in the journal Neuron.

Of course, Ms. Wilson says, studying single neurons is a long way from understanding what cannabinoids do in the brains of animals. For example, does blocking the docking stations (called cannabinoid receptors) so the molecules can't send their messages actually affect memory?

"What we're developing are tools that ultimately people who study behavior and psychology in rats, for example, can then take in to their laboratories and ... see how taking out this one feature could change how rats learn in a maze," she said.

The part of the brain linked to memory, the hippocampus, isn't the only place where cannabinoid receptors are found. In fact, they're widely distributed throughout the brain and the spinal cord. But they probably serve different functions in different areas.

It's the cannabinoids and their receptors in another brain region, called the hypothalamus, that appear to be involved in stimulating appetite. New research by George Kunos, of the National Institute on Alcohol Abuse and Alcoholism, and his colleagues helps explain why pot smokers get the munchies.

Using mice that had been genetically altered so they no longer had cannabinoid receptors, Dr. Kunos found that the mice ate less than normal mice after being deprived of food for a short time. The research was published last month in Nature.

Dr. Kunos said the level of cannabinoids in the hypothalamus is under the control of a fat-regulating hormone, called leptin. This hormone keeps tabs on the energy status of the body and helps maintain body weight. When leptin levels are low, cannabinoid levels appear to rise, stimulating appetite. Marijuana overwhelms the normal system and swamps the receptors, making pot smokers want to eat everything in sight.

The system that controls appetite is complex, though, because the mice without cannabinoid receptors ate normally and didn't lose weight if food was around. It was only after being deprived of food for a day that they were less hungry than their normal counterparts.

The appetite-stimulating effects of marijuana may be beneficial for patients with AIDS or those undergoing chemotherapy for cancer. Unfortunately, Dr. Kunos said, developing a drug that could mimic marijuana's munchie-inducing effects is problematic because it might be difficult to eliminate the drug's psychoactive effects.

However, says Dr. Kunos, "the opposite type of treatment, the use of a drug that blocks the receptor, which obviously has no abuse potential – that's more realistic." Such a drug might be used to reduce appetite.

To this end, Dr. Kunos and his colleagues studied what happened when they blocked the cannabinoid receptor in fat mice. Mice that are genetically bred to lack leptin chronically overeat and are obese. The researchers injected these mice with a compound that blocks cannabinoid receptors and found that it cut down the amount of food the mice ate and slowed their weight gain.

A French pharmaceutical company, Sanofi-Synthelabo, is already looking into this drug as a possible appetite suppressant for obese people. Dr. Kunos said human trials are still under way but initial reports are encouraging.

The drug is also being considered as a potential therapy for schizophrenia, because some researchers speculate that overactivity of the brain's cannabinoid system may contribute to schizophrenic symptoms. Trials are under way, says Dr. Kunos, "but the results are not known, and it's too early to tell if it would be effective."

The Nature and Neuron studies are among the first to demonstrate physiological effects of the brain's own cannabinoids. This system has proved hard to study because cannabinoids don't hang around in the brain very long.

If an animal is injected with anandamide, one of the brain's own cannabinoids, nothing much happens. Researchers were puzzled by this until they realized how fast anandamide breaks down – half of it is gone within five minutes.

But scientists at the Scripps Research Institute in San Diego are trying to make anandamide linger longer by preventing it from being broken down. Several years ago Dr. Cravatt, a biochemist, discovered an enzyme that breaks down anandamide, called FAAH.

Now he's bred mice that lack this enzyme, so anandamide sticks around longer in their brains. Dr. Cravatt couldn't discuss his findings because he's trying to get the work published in a scientific journal. But he hopes his mice will give researchers a much better understanding about what anandamide is really doing in the brain.

A colleague at Scripps, chemist Dale Boger, is trying to develop a chemical compound that would inhibit FAAH. Such a compound might be given as a drug to increase levels of anandamide in the brain. Dr. Cravatt says subtly adjusting the levels of anandamide in the body could increase appetite or reduce pain without causing the psychoactive effects of THC.

But Dr. Cravatt adds that the social stigma of marijuana may prevent any of these potential drugs from ever showing up on a pharmacy shelf.

"That's a hard pill to swallow," he says. "It's hard enough to get a drug that works – you don't want to worry about getting a drug that works and still not be able to distribute it. So I think we have to overcome that."

Diana Steele is a free-lance writer based in San Diego.