It wrecks neighborhoods, families and lives, and might be the most important public health problem faced by Western societies. Yet since chemists first isolated cocaine, morphine and heroin in the 19th century, physicians and scientists have struggled to explain the nature of addiction.
There is still much to learn, but with advances in genetics, medical imaging technology and neuroscience, scientists say they are closer than ever to understanding why some people who try drugs become addicted, and some do not.
"I think we made more progress in the last 10 years than in the previous history of mankind," said Frank Vocci, director of treatment and research at the National Institute on Drug Abuse, which spends $1 billion annually on drug research.
"We're a heck of a lot further along than we were 30 years ago," said Dr. Paul R. McHugh, a psychiatrist at the Johns Hopkins School of Medicine. That progress, he added, "tells me that we don't have to be quite as hopeless as we were before about addicts."
In the past decade, scientists have come to recognize that genetics plays a major role in all addictions.
It was long suspected that alcoholism was at least partly inherited because of its presence in some families and not others. But studies of addicts in Baltimore, Japan and elsewhere have shown that methamphetamine users, heroin addicts and other habitual drug users share similar variants of dozens of brain receptor genes.
One day, scientists say, genetic testing could enable drug counselors to warn parents if their children carry an unusually high risk of addiction, or tailor existing treatments to individual drug users. But the ultimate hope, of course, is that the genetics of addiction will help find powerful new treatments.
So far, the development of new addiction treatments has lagged far behind the basic science. "There have been modest, incremental improvements," said Dr. Solomon H. Snyder, a Johns Hopkins neuroscientist and psychiatrist who is one of the world's authorities on the biochemistry of addiction.
In general, he said, advances have come slowly because major pharmaceutical companies see little profit in tackling the problem.
But by defining what addiction is, researchers have helped the pharmaceutical industry identify what it calls "targets" for drug research - genes, proteins, neurotransmitters that could be modified to block the compulsive use of drugs.
One thing that addiction is not, scientists say, is a simple inherited illness. There is no single gene that inevitably leads to habitual drug use. Instead, some people appear to carry an array of genes that raises their risk of addiction.
"Nobody has to become addicted," said Dr. George R. Uhl, a clinical neurologist and chief of the National Institute on Drug Abuse's molecular neurobiology branch at Hopkins' Bayview campus.
"Genes have an influence on behavior," McHugh said. "They're not a determining influence on behavior, in that if you've got them there's nothing you can do about them. They are an influence."
Overall, researchers say, about half of an individual's susceptibility to addiction is inherited, while the other half is the product of a person's environment - which includes the pressures of family, peers and neighborhood.
Discussions of addiction usually focus on people living in the most desperate circumstances, in the poorest neighborhoods. But the problem, of course, extends far beyond the inner city.
A brother lost
Lee Krol was a skilled marine electrician, homeowner and father who lived in Pasadena. But he had a problem that anguished and mystified his family for most of his life. As a teenager, he began to drink and use drugs. While he would quit for a while, it was never for good. "There's nothing like this stuff," he once told his brother, Tom.
So his family was devastated, but not surprised, when they found the 50-year-old on the floor of the computer room of his home Dec. 7, dead of a heroin overdose. "I want him to be portrayed as a good person," said Tom Krol. "He just had a terrible disease."
Since the early 1970s, scientists have identified all of the brain cell switches, called receptors, which respond to addictive drugs. Using advanced imaging technology such as MRI machines and PET scanners, they have been able to watch as drugs alter the way the biochemical signals called thoughts and feelings are transmitted through the brain.
Addiction research has zeroed in on a group of brain cells in the nucleus accumbens, nestled deep within the brain, the location of what has been called the "pleasure reward" system. Many of the brain cells, or neurons, in this network communicate with each other with two of the brain's chemical messengers, serotonin and dopamine.
The system produces feelings of well being, the reward for engaging in actions such as eating and sex, vital to survival and reproduction. Illicit drugs, it turns out, switch on this system - specifically, by raising the level of dopamine available to neurons.
Dopamine receptors, scientists say, appear to play an important role in all three of the main features of addiction - tolerance, withdrawal and compulsive drug seeking.
Despite the recent advances in the lab, much of the way this system works remains a mystery, Snyder said. Recent research, though, offers some clues.
Using advanced imaging technology, scientists have discovered that people whose brains have a higher concentration of the so-called D2 dopamine receptor reacted with indifference to a mild stimulant - in this case, Ritalin - while those with fewer D2 receptors tended to enjoy the experience.
Dr. Nora Volkow, one of the nation's leading addiction researchers and director of NIDA, led studies showing that cocaine users have lower concentrations of D2 receptors than nonusers.
It's not clear whether people are born with higher D2 receptor densities, develop higher densities as a result of experience, or both. In a paper in the journal Nature Neuroscience in 2002, scientists at Wake Forest University showed that macaque monkeys that achieve high status in small groups tend to develop a higher concentration of D2 receptors. The D2 density of subordinate macaques did not change.
No simple answer
This work suggests that there is a link between low status, D2 density and vulnerability to addiction. But this picture may not be as simple as it seems, said Snyder, who helped launch modern addiction research in 1973, when he and his student, Candace Pert, discovered the opiate receptor.
When researchers in his lab exposed rodents to mind-altering drugs, Snyder said, they would typically find that hundreds of genes in the rodents became more active - raising, say, the number of receptors - and hundreds became less active.
"From our experience with rodents, D2 receptors went up, but probably another 299 things went up, too," he said. Tracking a single change in a single receptor does not establish a cause-and-effect relationship.
Still, some scientists say that advances in genetics research could have practical applications. Uhl, the NIDA neurologist at Bayview, points out that Naltrexone, used to block the effects of alcohol, works better for people with one form of a gene than another.
"If you have a genetic test that tells you the drug is twice as likely to be effective in this person than that one, you could focus the treatment in ways that are the most likely to have benefits," Uhl said. "That seems like a huge potential positive impact."
Drugs developed to treat other diseases are being used to help addicts. Smokers are often given anti-depressants, for example, to help them overcome their dependence on nicotine - which ranks with cocaine as the most powerfully addictive of the widely used drugs. (Without treatment, only one out of 20 smokers quits successfully, researchers say.)
One of the most successful treatments for habitual drug users, said Michael Gimbel, a former heroin addict and director of substance abuse at Sheppard Pratt Health System in Towson, are Alcoholics Anonymous-style "12-step" programs, in which addicts guaranteed anonymity encourage one another to overcome their dependence.
Many drug users will need more intensive, residential treatment. Tom Krol said his brother, Lee, needed residential treatment, but could not afford to take the necessary time off from work.
The public, frustrated by the seeming intractability of addiction, is reluctant to pay for expensive treatment programs, researchers point out. As a result, there is a chronic shortage of spaces or "slots" in such programs nationwide.
Snyder of Hopkins said that Maryland's General Assembly is considering a bill to spend $125 million over five years on stem cell research. Why, he asked, aren't legislators seeking a similar crash program to develop new treatments for drug abuse?
Curbing addiction would have direct relevance to one of the most important health challenges facing Baltimore and other Maryland communities. Such a program, he said, would have a better chance of success than many other research efforts, because so much of the groundwork has been laid.
The prospect of new stem cell treatments "is a way-, way-, way-off hope," Snyder said. "If we did something about drug addiction, if we had research focused on therapies, there we would have a payoff in the much-nearer term."