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A clearer picture of marijuana Research: Studies are exploding as scientists pinpoint the things that set this drug apart from all others.

THE BALTIMORE SUN

A few major discoveries in the past decade are giving scientists a clearer idea of the workings of marijuana.

The discoveries confirm one long-standing hunch: Marijuana is different from other drugs, acting on its own abundant network of chemical receptors.

That knowledge has offered the promise of new drug therapies that might someday help correct faulty memories and poor motor coordination. While some scientists toil on those fronts, others are learning about the damage pot may cause in the lungs and its slightly suppressive influence on the immune system.

"It's exploding," Dr. Donald Tashkin of the University of California, Los Angeles, says of today's marijuana research. "Now we have the tools."

Tashkin's findings in his work as a research physician are some of the most dire for chronic marijuana smokers.

For more than a decade, he has been comparing the lungs of pot smokers, cigarette smokers and nonsmokers, looking for changes in the airways and cellular damage that may lead to lung cancer.

His pool of volunteers -- he began with more than 300 marijuana smokers -- undergoes regular breathing tests and other procedures, including the removal of lung tissue for study in the laboratory.

The preliminary findings show that pot smokers who inhale three or four marijuana cigarettes -- joints -- a day suffer from chronic bronchitis as often as cigarette smokers who light up a pack or more a day.

In each case, Tashkin says, the pot smoker and the cigarette smoker also show ominous changes in the linings of the trachea and bronchial tubes.

At first, the cilia-covered cells that sweep soot out of the lungs begin to die off, replaced by mucous-producing cells and other tissue cells that proliferate far beyond normal.

"The cells are disorganized," Tashkin says. "It doesn't mean they're going to turn into cancer, but it's on the way to cancer." Tashkin says the greatest damage is evident in the lungs of those who smoke both marijuana and tobacco.

Unfiltered chemicals

Marijuana smoke contains many of the same cancer-causing chemicals as cigarette smoke, but a loosely packed, unfiltered joint may deposit four times more tar in the lungs than a cigarette.

Evidence also shows that marijuana smoke is more harmful than tobacco smoke to the immune cells in the lungs that attack burgeoning tumors.

Those findings, which Tashkin presented at a recent National Institutes of Health symposium on marijuana, are considered preliminary, he says.

Other apparent breakthroughs in understanding marijuana's effects on the brain date to 1988, when Allyn Howlett of St. Louis University discovered the chemical receptors that react to delta-9 tetrahydrocannabinol, or THC, the compound in marijuana that produces a high.

Until the receptors were found, some scientists speculated that pot, like alcohol, was a "dirty" drug, producing its effects by gumming up the works inside any number of cells and systems. The existence of the receptors proved otherwise, setting marijuana apart from any other kind of substance, including heavily addictive drugs such as heroin and morphine.

"It's completely different from all the other drugs," says Miles Herkenham, a brain researcher at the National Institute of Mental Health in Bethesda, who helped map the location of the cannabinoid receptors in the early 1990s.

Regulating systems

Cells embedded with the receptors are inhibited from functioning when exposed to the THC molecule. Scientists theorize that the natural purpose of the receptors may be to help regulate other systems in the body's complex network of checks and balances.

Cannabinoid receptors are concentrated most heavily in the cerebellum, the part of the brain that controls motor coordination, and in the hippocampus, which governs learning and memory.

Large numbers are also found in the cerebral cortex, the seat of higher thinking, and lesser numbers are scattered in the immune system. They are largely absent from the brain-stem regions that govern heartbeat and respiration.

The imbalance enables scientists to account for the loss of coordination and the distorted perceptions that are characteristic of a marijuana high.

Pot's influence on the immune system seems relatively subtle, Herkenham says. In those whose immune responses are already poor, marijuana could perhaps be harmful. Advocates of marijuana use in medicine, however, say it helps to reduce pain and nausea and stimulate the appetites of AIDS and cancer patients -- benefits that may far outweigh its downside.

"The paucity of receptors in the brain stem is crucial for explaining why it's a 'safe' drug," Herkenham says. "It's impossible to take a lethal overdose."

Locating the receptors has given scientists far keener insights -- but no clear answers -- in their efforts to determine whether marijuana is addictive.

Different receptors

Usually, drugs that produce an intense craving -- heroin, cocaine, morphine and nicotine, for example -- act upon receptors in the dopamine system, a circuit that regulates nerve activity in the brain, Herkenham says. A theory exists that any "drug of abuse" affects the dopamine system, and marijuana does not.

Still, some scientists suggest that if dopamine receptors can become accustomed to a chemical high, so can cannabinoid receptors, even if the result is more subtle.

Evidence that marijuana is addictive has been elusive in part because THC is readily stored in body fat.

Pot smokers who quit are often weaned off the drug slowly as small amounts continue to filter into the bloodstream.

A few years ago, research grew out of another significant advance: Scientists discovered a compound that prevents THC from binding to the receptors. The blocking compound made it possible for researchers to shut off THC's effects on the brain almost as if they were turning off a water spigot, despite THC's presence in fat tissue.

The discovery enabled Dr. Billy Martin of Virginia Commonwealth University to demonstrate what he called "a dramatic withdrawal" in laboratory rats. Martin and Dr. Michael Walker of Brown University performed almost identical studies in 1994.

People who quit smoking pot may not realize they are going through withdrawals; they may think they are catching the flu.

The National Institute of Drug Abuse, which funds most of the marijuana research in the United States, estimates that 100,000 people seek treatment every year for pot dependency.

But marijuana research has been hampered by decades of emotionalism and politics.

Scientific disclosures about the drug's purported effects on memory, reproduction and childhood development have been nebulous in many cases, inviting any number of interpretations. Even scientists complain that some results are hyped, twisted or based on sketchy data.

One researcher now claims to have evidence that heavy pot smokers perform more poorly on psychological tests than light smokers, even when both groups are sober.

Those findings were based on two groups of college students who were tested 24 hours after using marijuana, says Dr. Harrison Pope, who conducted the research at McClain Hospital in Belmont, Mass.

Pope is not sure how to account for the results. They may indicate a withdrawal effect, or that THC lingers in the brain, or that heavy users actually suffer some mild brain damage.

"You'd think by now we would have some idea which," he says. "It's a testimony to how little we know.

"We're trying to find these fundamental things relatively late in the game."

Pub Date: 12/27/96

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