Temple Magazine

Drug War Stories

Temple faculty members wage a war on drugs their own way—with groundbreaking research about the biology of addiction.

story by Laurence Roy Stains

PHOTOGRAPHY BY RYAN S. BRANDENBERG

Scott Rawls sits in his eighth-floor office overlooking Temple University Hospital, but his mind is a few hundred miles away. He is back in coastal North Carolina, where he grew up; he is sitting at the dinner table watching his father smoke Lucky Strikes. That was his dad: A Korean War veteran, a man who succeeded in life despite an eighth-grade education, but a man who was hooked on nicotine. "He smoked until he died—and he died at age 62 of COPD [chronic obstructive pulmonary disease]," Rawls says in a soft Carolinian drawl. "His lungs were basically shot. He was a tough guy, the toughest man I've ever met. But he could not quit smoking."

Rawls pauses. "That's what got me into this field."

And that is what brought him to North Broad Street. An associate professor of pharmacology, Rawls is one of 30 faculty members in Temple's Center for Substance Abuse Research (CSAR). Founded in 1998, it consolidated a dozen of its laboratories in the Medical Education and Research Building at 3500 N. Broad St. last summer—
a new home befitting its status as one of the nation's largest science centers investigating the fundamental causes of drug addiction.

These days, Rawls is in hot pursuit of a novel way to unhook the brain's reward center from the grip of street drugs like cocaine, and prescription opioids like OxyContin and morphine. Seven years ago, he began investigating a potential medication—an antibiotic in the same class as penicillin—that showed promise as an aid in reducing drug cravings and relapse. He and his colleagues at Temple and elsewhere then tested the drug (and later, a chemically similar drug, clavulanic acid), their research supported by three major National Institutes of Health grants. And because the Food and Drug Administration (FDA) has approved clavulanic acid as a drug that prevents resistance to antibiotics—it is a part of the common toddler-ear-infection treatment Augmentin—there is no regulatory marathon to be run. So now Rawls is ready to team with clinicians to take the research to the next level: human trials with cocaine and heroin addicts. Successful results could be implemented in drug treatment facilities relatively quickly.

That would be a very big deal. Right now, there is no known cure or FDA-approved treatment for cocaine addiction. There is only its horrific impact: street crime, warring cartels, early deaths and wasted lives.

RISK, REWARD

"This is your brain on drugs," taunts the voice-over in a 1987 anti-drug public service ad as a video of eggs frying in a pan is shown. Here's a more scientific explanation: Drugs deliver "highs" by affecting the brain's neurotransmitters, which are the chemicals that allow the neurons—the cells of the nervous system—to communicate. When this happens in the nucleus accumbens, which is the brain's "reward center," one feels very...well, rewarded.

What is less understood is the exact mechanism of addiction. "We're just beginning to understand what happens in the brain on a molecular level," says Ellen Unterwald, professor of pharmacology and director of CSAR. "There's some sort of molecular switch that makes the behavior compulsive. You know it's harmful, but you can't stop yourself."

In the drug-addicted brain, life's little rewards no longer muster a neurotransmitter surge; the brain has been rewired to the point where it essentially listens to the drug—and only the drug—instead of the user. Because the brain's basic chemistry is altered, neuroscientists now regard addiction as a brain disease.

Some researchers have publicly predicted that we are only one or two decades away from an anti-addiction pill. "Wouldn't that be nice," Unterwald says. "But I don't believe there will be one drug that cures all addiction," just as no one drug will likely be a cure for cancer.

Every drug, and every drug addict, is different. In the future, successful strategies will act on multiple neurotransmitters to reduce drug cravings; by necessity, they also will be able to keep former addicts from going back to the drug. A major hurdle for addicts is the fact that environmental cues—old friends or places where they used to get high—can cause them to relapse with an astonishing frequency.

Those are all puzzles to be solved, which is why the National Institute on Drug Abuse (NIDA) pours hundreds of millions of dollars into drug-abuse research. As one of 14 "Core Centers of Excellence" in the nation, Temple receives a chunk of that NIDA funding. It also receives grant money from other federal agencies, foundations and pharmaceutical companies. All told, roughly $3 million in annual grant money infuses CSAR. So researchers at Temple are hardly pursuing a single line of scientific inquiry. In fact, there are several lines of inquiry—several stories, really—veering off in very different directions.

For instance, Scott Rawls' research targets a pair of neurotransmitters working in tandem: glutamate, an excitatory brain chemical that acts as a "gas pedal," and GABA (gamma-aminobutyric acid), an inhibitory transmitter, which acts as the "brakes." Typically, the brain of a cocaine addict experiences broad swings in the balance of glutamate and GABA levels.


doctors in lab

Left to right: Toby Eisenstein, Ellen Unterwald and Scott Rawls conduct research in the cross-disciplinary Center for Substance Abuse Research, housed in the Medical Education and Research Building.

Rawls is using clavulanic acid to activate the glutamate transport system, which will enable cells in the brain to absorb glutamate and normalize the hyperactivity that underlies cocaine's effect. Ideally, the process will reduce the craving and motivation to sniff a new line of white powder.

Unterwald's research projects focus on a better-known neurotransmitter: dopamine, which regulates pleasure. Currently, Unterwald is investigating why post-traumatic stress disorder
(PTSD)—a major health problem among U.S. soldiers returning from combat—makes the brain more vulnerable to drug addiction. She tests how dopamine levels in the brain fluctuate with stress. Not surprisingly, stressed brains produce less dopamine, which means the loss of some ability to feel pleasure. Her next step is to see whether those stressed brains can regain normal reward-center functioning when given L-dopa, a precursor of dopamine that is used to treat Parkinson's disease. It is easy, then, to imagine where this might be headed: Perhaps returning vets with PTSD will one day receive treatment to restore their dopamine levels as a preventive measure against drug addiction.

INTO THE UNKNOWN

While Rawls and Unterwald gain national acclaim for their work on addiction, Toby Eisenstein is moving beyond the idea of "medical marijuana" as she probes the connections between the body's nervous and immune systems.

In the 1990s, researchers discovered that marijuana is not just a brain-altering drug. Yes, it acts on the CB1 receptors on the brain's neurons to produce a psychoactive effect, but it also acts on CB2 receptors that are present on most cells of the immune system—that is, our white blood cells. (Receptors are molecular "locks" on the surfaces of cells that admit only certain external compounds, like drugs or neurotransmitters.) Marijuana dampens the body's immune response. It is "immunosuppressive," to use a 50-cent word.

Though suppression of the immune system sounds negative, it is quite positive when our systems go awry. There are times when the body's inflammatory response to injury actually causes further tissue damage; that is the case in the aftermath of strokes and spinal-cord injury. In the case of autoimmune diseases like multiple sclerosis (MS)—in which the body's own immune system sends T cells to destroy the fatty myelin sheath around nerve cells in the brain—suppression is the very goal of treatment. Immunosuppression also is a necessary follow-up to skin grafts and organ transplants; it keeps the body's own T cells from attacking the unfamiliar donor tissue.

In effect, early marijuana research pointed out an immune-system receptor that could then be "switched off" with synthetic drugs—compounds that, unlike marijuana, could affect the immune system without also producing a high.

Eisenstein, professor of microbiology and immunology in the School of Medicine and co-director of CSAR, currently examines those synthetic compounds. In her most recent work, preliminary results show that the compounds can retard skin graft rejection. Future experiments will attempt to ramp up this therapy for use with human organ transplants. Today, organ recipients must take medication indefinitely to keep their T cells from attacking new organs, and the standard medications are significantly toxic and eventually cause damage to the kidneys, pancreas and central nervous system. Used in conjunction with standard treatments, a CB2 therapy might allow for reduced doses of those toxic medications.

Related research is being conducted by Ronald Tuma, CST '75, professor of physiology and associate professor of neurosurgery, and Doina Ganea, Earle H. Spaulding Chair of Microbiology and Immunology. They study the way MS attacks the myelin sheath of nerve cells, causing motor dysfunction and loss of muscle control. They induce an MS-like condition, then administer a synthetic compound that acts on the CB2 receptors and successfully reduces the severity of motor dysfunction in the legs. In yet another experiment, Tuma has used the CB2 compound to reduce by 90 percent the size of brain-tissue damage because of a stroke.

All these possibilities—for drugs that fight MS, facilitate organ transplants and reduce the severity of stroke—stem from basic inquiry into the far-reaching effects of marijuana on the brain and the body. "We do basic science here," Eisenstein says. "It's exploration into the unknown. If we knew where we were going, it would be engineering."

Laurence Roy Stains is an associate professor of journalism at Temple. He is an award-winning writer who has contributed to numerous national publications, including The New York Times Magazine, Rolling Stone, GQ, Men's Health and many others.