Finding safe and effective weight-loss medications has long been a goal for drugmakers and physicians alike—roughly one third of American adults meet the clinical criteria for obesity, according to the Centers for Disease Control and Prevention. This year the U.S. Food and Drug Administration has been reviewing three new antiobesity drugs for government approval. Given the field’s checkered past, however, major questions remain about the risks of pills that pare away the pounds.

Although drugs that seem promising early on sometimes prove ineffective or downright dangerous after they hit the market, the obesity field has seen more than its share of failures. In the 1960s amphetamines were touted as the answer to weight loss until they proved habit-forming. The mid-1990s witnessed the disaster with fen-phen (fenfluramine and phentermine), which caused heart valve disease. Then just a few years ago the FDA denied approval for a new weight-loss drug after it was linked to suicidal behavior.

To date, only two drugs are FDA-approved for long-term treatment of obesity, and they are not without concern. Earlier this year the European Union banned one of the compounds, sibutramine, or Meridia, after new reports of heart attack and stroke. The other drug, orlistat, now sold over the counter as Alli, causes gastrointestinal distress and has been associated with liver damage in some patients.

Nevertheless, researchers think drugs are the way to go and hope medications will one day replace costly and potentially dangerous surgeries such as gastric bypass. The situation is not unlike that for hypertension before the middle of the 20th century: until the advent of beta blockers in the 1960s, physicians removed sections of peripheral nerves to control high blood pressure. Today physicians treat hypertension almost exclusively with medication. Developing drugs for a chronic condition, whether it is obesity or hypertension, is challenging, though. “Most chronic diseases have lots of redundant mechanisms, so it is unusual to find a ‘magic bullet,’” explains Frank Greenway, chief of the outpatient clinic at the Pennington Biomedical Research Center in Baton Rouge, La.

Obesity has a neuropsychiatric component, which makes it especially troublesome to treat. Each of the three new drugs facing FDA review targets the brain differently. One drug, called Contrave, takes aim at the brain’s reward pathway, whereas the other two compounds affect brain areas that are involved with appetite. All three drugs appear to induce long-term weight loss. The concern is that like antiobesity drugs before them, which also targeted the brain, they could cause unwanted effects on the central and peripheral nervous systems.

Lorcaserin, one of the three new drugs, affects serotonin, which involves multiple brain processes besides appetite, including emotion and cardiovascular regulation. The company behind lorcaserin, San Diego–based Arena Pharmaceuticals, has gone to great lengths to show that the chemical does not cause the serotonin-related heart valve problems associated with fen-phen. Yet the drug could still lead to depression or increased cardiac risk factors, such as high blood pressure, especially if patients combine it with other drugs in an attempt to hasten weight loss.

The other two drugs, Contrave and Qnexa, could also cause unwanted neurological side effects. Bupropion, an ingredient in Contrave, has been linked to anxiety; topiramate, Qnexa’s main ingredient, has been associated with memory problems. The companies behind Contrave and Qnexa—Orexigen in La Jolla, Calif., and Vivus in Mountain View, Calif., respectively—maintain that by combining the drugs with other agents, they have brought the doses below levels that would trigger adverse reactions. “Finding the right dosage is key,” says Barbara Trou­pin, senior director of medical affairs at Vivus.

But problems could still occur, considering that patients with existing mental health issues are often excluded from obesity drug trials, so side effects not seen in trials could emerge when this population uses the medication. Such a situation may have occurred in 2007, when Sanofi-Aventis hailed Rimonabant, another neurotargeted drug, as a safe and effective weight-loss treatment. “The press releases looked great,” Greenway remembers. Shortly after the drug was released in Europe, however, reports of Rimonabant-related suicides began trickling in. The drug was never approved in the U.S. and was later recalled in Europe.

As a result, the FDA will likely view the new antiobesity drugs with caution. In July an FDA advisory panel narrowly voted against Qnexa, citing concerns over side effects. The FDA is not required to act on the panel’s recommendation, though.

Ed J. Hendricks, a physician who runs a weight-loss center in Sacramento, Calif., hopes at least one of the three drugs will be approved. “As the pathways behind obesity are better understood, the drugs are getting more specific,” he says. The question is whether they will act specifically enough and prove safe for wide use.