In describing her first crack cocaine high, Alice said, “I took a hit, like sucked it in really quick and let it make its way to my brains. It didn’t take but a minute. I could feel my heartbeat getting faster. My eyes and my mouth went dry. I was sweating all over . . . my muscles were all tight but it didn’t hurt. It’s like you get to go to heaven for a second. No kidding, I thought I was gonna die, but a pleasant death.”

Addicts often remember their initial relationship with a drug romantically, recalling a burst of euphoria, energy, or confidence. If they’re using with other people—a group of friends, a relative, a lover—they recount heightened feelings of camaraderie, intimacy, and emotional awareness. Some say that, when high, they had more meaningful conversations, more intense sex, or a spiritual awakening.

Inevitably, though, the high bottoms out, the glow fades, and the relationship sours. Even then, addicts can’t stop using.

“You keep on chasing that first high,” says Marsha. “The next time doesn’t feel as good, and you just chase a feeling. Chasing makes it so you can’t control your habit.”

Understanding the internal experience of addicts is integral to understanding addiction itself, says Claire Sterk, an Emory researcher in the Rollins School of Public Health who quoted Alice and Marsha in her book Fast Lives: Women Who Use Crack Cocaine.

“I ask them to describe to me what happens before they take it, during, and after—the whole process,” says Sterk, who has studied addicted populations for twenty years. “You can’t do that in a lab looking at isolated substances or through animal studies.”

Determining which parts of the brain are affected by drugs like cocaine and finding ways to block the feelings that lead to cravings and dependency is at the forefront of current addictions research. For successful treatments to be devised from this work, however, findings must be taken out of the lab and applied in the real world.

“That’s where things get complicated,” says Sterk, who researches such topics as multi-generational drug use and mental health, the increasing popularity of club drugs like ecstacy, and the relationship between drug use and sexually transmitted diseases.

Sterk is one of a number of Emory researchers—in fields from public health to neurology—who are studying the biological and social roots of substance abuse. From pinpointing the pathways drugs follow in the brain to determining how cravings arise by using guided imagery with recovering addicts, these researchers are looking for clues about effective ways to prevent and treat addictions.

Most of the studies focus on cocaine, an especially addictive stimulant that seems to create long-term changes in the brain. About one and a half million Americans are thought to be addicted to cocaine, according to the National Institute of Drug Abuse, which funds much of the research being conducted on addiction.

Michael Kuhar, the Charles Howard Candler professor of neuropharmacology at Yerkes National Primate Research Center, is leading a team of researchers trying to find “cocaine analogues”—drugs that will dull or eliminate the desire for cocaine, much as methadone does with heroin.

Addiction, says Kuhar, is “the drive to repeat something in spite of negative consequences for you personally, your family, or your community.” Much like heart disease, he says, drug addiction can be examined not only from a medical perspective but through genetic, environmental, and behavioral lenses. Still, he believes the answer to why people become addicted to drugs is writ at the molecular level and remains in large part a mystery.

“We know drugs bind to certain receptors and cause certain changes. But we don’t know all of the changes and which ones are critical,” he says. “We believe it is the accumulation of these changes that is important in addiction, since the duration and frequency of drug use is related to the magnitude of dependence.”

Drugs impact deep, primitive portions of the brain, Kuhar says, which means their use is “not simply under the control of reason—motivational desires and urges become dominant.”

Significantly, addictive drugs stimulate the same areas of the brain as food, water, and sex. “Some drugs make you feel good, but that’s not necessarily why people become addicted,” Kuhar says. “The whole reason reward and reinforcement pathways exist in the brain is for survival. Certain drugs ‘turn on’ those areas of the brain, and those drugs are the ones that make you want to take them again and again.”

In researching the effects of cocaine, Kuhar and his colleagues discovered the exact mechanism by which the drug disrupts the brain’s levels of dopamine—a chemical that helps brain cells communicate and that in larger-than-normal concentrations can cause feelings of euphoria. Cocaine raises dopamine levels in the brain by acting almost like a stopper in a drain. With chronic cocaine use, the dopamine system can become “reset,” and can take months or years to return to normal even after drug use has stopped.

The next step is to develop medications that will help cocaine abusers. Kuhar and collaborators from the Research Triangle Institute in North Carolina developed a class of drugs called phenyltropanes, which affect the same brain systems as cocaine and related drugs but have lower potential for abuse and minimal side effects and toxicity.

Once in the brain, these cocaine analogues bind to the same dopamine transporters that cocaine targets but, because they enter the brain more slowly and are longer-lasting, it is hoped that users won’t get the rush.

After selected analogues were tested in rats, Leonard Howell, a behavioral neuroscientist in psychiatry at Yerkes, tested the drugs in squirrel monkeys that had been trained to self-administer cocaine. The animals’ cocaine use went down. Phenyltropanes, says Howell, appear to allow a gradual restoration of normal dopamine function, avoiding the “precipitous highs and lows . . . that send people running back to their habit.”

Cocaine cravings can feel overpowering, says addiction psychiatrist Karen Drexler, an assistant professor in Emory’s School of Medicine who works at the Atlanta Veterans Affairs Medical Center (VA).

Drexler, who directs the substance abuse program at the VA, is grateful for the methadone clinic on the hospital’s ground floor, which opened this summer. Thirty-four recovering heroin addicts visit the clinic to swallow a daily dose of the drug, which binds with the brain’s opiate receptors but is longer-acting and doesn’t provide the same rush. These recovering addicts can take methadone—even though it is addictive as well—for their whole lives, Drexler explains, just as a diabetic would take insulin.

“It is counterintuitive, but it’s proven to be immensely effective at reducing crime, and keeping them healthy and out of jail,” she says. “They go from being drains on society to productive members of society.”

There is no such alternative yet for cocaine addicts in recovery—the bulk of Drexler’s case load.

“About 75 percent of our patients who present for help with their addictions says their drug of choice is cocaine. The thing that’s really devastating about cocaine is that people are able to stop taking it fairly easily—they just can’t stay off it,” she says. “When people are using alcohol or heroin heavily then stop, they get sick and have withdrawal that can be life-threatening. With cocaine, that doesn’t happen. People may be tired and depressed, but they aren’t terribly sick. They can do just fine until, say, their next paycheck comes. Then they have a very strong craving that seems irresistible.”

Drexler is using positron emission tomography (PET) to determine the areas of the brain that are most active during these periods of desire for the drug. She uses personalized scenarios based on interviews with the addicts that detail the environmental and internal cues—feelings, smells, tastes, people, places—associated with past drug use. The volunteer is asked to mentally re-enact the scene as they listen to it on headphones, while a ninety-second brain scan is conducted to see which neuropathways light up.

Here is the transcript of a scenario from one of Drexler’s clients:

It’s Saturday night and I’m ready to do my usual thing. I want more than anything to feel the rush I used to feel. . . . I’m ready to make the buy. . . . Once I get to his house we chill for a minute and then I’m on my way home. Now, as quick as I can, I drive home, lock all the doors, turn on the TV and radio, and take a hot shower. Now I’m ready and I can feel the beads of perspiration all over—I am so restless. God, just thinking about getting high makes my heart beat faster. I get all my utensils together, get comfortable on the couch and get ready to take the first, incredible hit. Finally I take my lighter out of my pocket, put it to the stem and smell the first burning of the stuff that’s going to take me to the next level.

The areas of the brain that respond, Drexler found, are the amygdala (stimulus and reward), the nucleus accumbens (incentive and motivation), and the anterior cingulate cortex (anticipation.) These are essential pathways, also activated during activities like eating and sex. “The brain,” she says, “starts to think that cocaine is essential to survival.’’

In support groups for recovering addicts at the VA, Drexler often lectures with a model of the human brain, pointing out the central areas responsible for cravings. One recent morning, six clients gathered in a small room on the fifth floor, listening intently.

”It seems baffling, how a substance can get a hold of and control your life instead of you controlling the substance,” Drexler said. “I want to help in your understanding of addiction as a brain disease, not just a bad habit or a moral problem. A lot of times, we struggle with shame. But it truly is a disease, like diabetes or heart disease.”

She tells the group about twin studies and the strong hand genetics seems to play in addictions.

“I’m a triplet,” says Michael, a calm, soft-spoken man who said he held a job but used to binge on weekends. “My sister doesn’t even drink. But my brother and I were curious about drugs.”

Elaine, a talkative mother who has struggled for many years with drugs, said, “As my addiction progressed, and my life became unmanageable, I would still want more cocaine. After the first hit, I was on a mission 24/7. I knew the only things that could stop me were death or the police. I was high-risk to start with—it runs in my family. But I have daughters, and I don’t want my angels to walk the road I’ve walked.”

Anthony, a middle-aged man who smiles frequently and calls Drexler “doc,” was full of questions about the nature of addiction. “Alcohol triggers everything for me,” he said.

“You’re not alone in the alcohol-cocaine connection,” Drexler answered. “Two things happen when you drink. One is that you prime the pump—your brain gets the message that it’s time for you to use. And secondly, it decreases your ability to use your frontal cortex and think logically.”

The group started talking about the valuable parts of their lives they had sacrificed to drugs: jobs, family, money, friends. “Right. Drugs have hijacked those pleasure pathways,” Drexler said.

When payday came, or an event to celebrate, or stress, the solution was to turn to the drugs. “You want what you want when you want it,” said Darren, who said that while he was using he was on a continuous quest to find new and better highs.

“Associative learning is working against you,” Drexler replied. “But it can work for you, if you learn to recognize high-risk situations.”

While other researchers are focusing on areas of the brain that respond to cocaine and how addicts can resist these intense cravings, Winship Distinguished Research Professor and Chair of the Department of Chemistry Jay Justice is trying to determine which strands of proteins, down to the exact amino acids, are targeted by the drug.

Neurotransmitters like dopamine, norepinephrine, and serotonin are affected by drugs of abuse as well as by therapeutic drugs such as antidepressants, says Justice, who teaches the course “Chemistry of Drugs in the Brain.”

But cocaine is especially insidious. “The brain adapts to the continued presence of the drug,” he says. “You get a real problem when you take it away . . . cravings, relapses. It’s not the same brain anymore.”

The brain itself seems remarkably attuned to these effects, says Justice. In research conducted by his team, rats that were trained to press a lever to administer cocaine to themselves would adjust the amount if researchers doubled or halved the dose. “Somehow,” he says, “they knew what was going on and regulated the drug.”

Addiction, Justice believes, is a brain state. “This is not an existential problem that exists in the ether,” he says. “I don’t believe in a brain-mind dualism. Everything has a molecular basis.”

Justice walks through his lab, where graduate student Sara Wirtz is “prepping membranes” in petri dishes. This involves spinning cells down and getting rid of “all the stuff on the inside,” says Wirtz, so experiments can be performed solely on the proteins. Beakers of bovine serum, resembling pitchers of cherry Kool-aid, are used as the medium for growing the cells.

The team has narrowed the search to a nine amino acid sequence. But there is much they still don’t understand, such as why some people become addicted and others don’t.

“It seems that, for certain individuals, their brain says, ‘This is just what I was looking for,’ and they’re off and running,” Justice says. “In others, they think, ‘That was interesting,’ and then go and wash the car.”

By examining early-life risk factors like abuse or neglect, Professor of Psychiatry Paul Plotsky is attempting to discover the biological basis for vulnerability to depression, addiction, and other mental disorders. His studies of baby rats who were repeatedly separated from their mothers at a young age showed that the stressed rats had a greater susceptibility to drug and alcohol use.

“The early environment clearly contributes to the development of these disorders, by causing permanent, measurable changes in brain chemistry,” Plotsky says.

As opposed to determining an individual’s destiny, genes seem to instead create an “envelope of potential outcomes” that are then narrowed by external factors.

Still, the human genome project offers a possible diagnostic avenue that might one day settle the long-standing debate over whether certain people are genetically predisposed to abuse drugs or alcohol.

From the newly sequenced human genome, scientists have shown that humans’ genetic codes are about 99.9 percent the same. Individuals carry only about fifty different mutations that influence their health, making them, for example, more vulnerable to heart disease or less susceptible to certain types of cancer.

Stephen T. Warren, William Patterson Timmie Professor and chair of Emory’s department of human genetics, which occupies the third floor of the Whitehead Research Building, says genes do seem to play a role in substance abuse.

“If we can identify those genes and the variance, that will be both useful clinically to treat addiction and also potentially to flag individuals who might be prone to the effects of certain compounds,” Warren says.

Certainly in the coming decade, he says, there will emerge a great deal of new insight into the genetics of addictions.

“Finding the genes that influence addiction opens up a lot of possibilities. Perhaps designer drugs will be developed that will moderate addictive tendencies. I could envision genetics addiction counseling,” he says. “Then again, changing people’s lifestyles is the hardest thing you can do in medicine. There’ll be gallant efforts, but the outcome is unclear.”



© 2002 Emory University