By Michael Craig Miller, M.D.

Remember “Just say no”? It was a slick motto, but a terrible remedy for drug and alcohol dependence. Decades later, more than 20 million Americans are still wrestling with addiction. This disease costs the nation almost $500 billion a year — more than diabetes and cancer combined. The problem is not flawed character; it’s skewed brain function. Fortunately, scientists are now well on their way to understanding how addiction changes the brain, and this knowledge is starting to yield treatments that work.

Addictive substances hijack the brain’s reward system, weakening our resolve to make wise choices even when painful consequences are sure to result. Specifically, they stimulate the release of the chemical messenger dopamine into a region of the brain called the nucleus accumbens. Cocaine and other stimulants cause this change directly. Other substances alcohol, narcotics, nicotine and marijuana — act indirectly. But in each case, the sensation is self-reinforcing. Feel it once and you want to feel it again.

This common pathway begs for a magic-bullet treatment, but the cycle of addiction is actually more complicated. It involves multiple chemical messengers, not just dopamine. The good news is that each of these messengers offers a possible target for treatment, and researchers are taking aim at them. The clearest recent advance is a new group of medications that work to combat craving. The archetype, a compound called naltrexone, reverses the pleasurable effect of narcotics like heroin. It also slows the release of dopamine in the nucleus accumbens. Recovering alcoholics tend to experience less euphoria when they drink while taking naltrexone, and their chances of staying in recovery improve. But the drug is far from curative. It doesn’t completely extinguish the desire to drink, and people who lack counseling and support often have trouble taking it every day. A new long-acting form of naltrexone could reach the clinic next year, enabling patients to get a month’s worth of treatment in a single injection.

That’s just the beginning. Last year the FDA approved a drug called acamprosate, which reduces craving by slowing the release of the chemical messenger glutamate. Some experts are also hopeful about topiramate, a migraine and seizure drug that boosts a signaling substance called GABA (gamma-aminobutyric acid). Yet another candidate is ondansetron, a serotonin blocker used to treat nausea in cancer patients. Studies suggest it can help cut alcohol consumption in people who take up drinking early in life.

While pursuing better treatments, researchers are also tackling the question of who gets addicted, and why. Heredity leaves some of us more addiction-prone than others, possibly because we metabolize drugs at different rates or respond more strongly to their effects. The research suggests that genetic differences may also affect our responses to treatment. A few studies have found that patients with a family history of alcoholism are more responsive to naltrexone than people without a family history. In a recent study, patients who had a gene variant dubbed Asp40 got more benefit from naltrexone than those with a different version of the gene. Markers like these, once better established, will help doctors figure out which treatments are best for individual patients.

We’re still a long way from pills that will make treatment easy. Long-term strategies are essential even when medication works because the affected brain circuits don’t return to normal right away, if ever. We now know that treatments combining medication and psychotherapy work better than either strategy does by itself. Next year, an eight-year study called COMBINE (Combining Medications and Behavioral Interventions) will provide the best evidence yet on how to weave drugs and therapy into a comprehensive treatment plan. Bitter experience may temper our hopes. But if we can finally begin to understand this illness instead of demonizing the victims, we may come up with approaches that help.