Over-the-counter packages of Nexium, Prevacid and Prilosec tell you to take the pills—known to doctors as proton-pump inhibitors, or PPIs—for just two weeks at a time unless otherwise directed by a physician. Yet drugs of this best-selling class prevent heartburn and ease related ailments so well that patients—particularly those who suffer from a condition called GERD (gastroesophageal reflux disease)—are often advised to take the medications for years. By decreasing acid production in the stomach, the agents prevent the caustic liquid from backing up—or refluxing—into the esophagus, where it can cause pain and can damage the food tube's delicate lining.

In recent years, though, safety questions have been raised about prolonged use of the blockbuster drugs. (The medications appear to be safe when taken for a short period, as directed.) Some studies, for example, have linked continuous treatment with proton-pump inhibitors to serious infections caused by the bacterium Clostridium difficile. Presumably something about lowering the acid environment of the stomach allows the pathogens to survive when they otherwise might not. Other investigations suggest long-term changes in the stomach's acid content can lead to improper absorption of several vitamins—such as B12—and minerals, triggering bone loss, among other ill effects.

Perhaps the biggest surprise came last year when two studies linked the regular use of proton-pump inhibitors to conditions that were seemingly unrelated to the acid levels of the stomach. One of the studies, published in JAMA Neurology, found that the drugs increased the risk of developing dementia, including Alzheimer's disease; the other, published in JAMA Internal Medicine, suggested a greater risk of kidney problems.

The papers did not prove that PPIs cause the problems. But some researchers have nonetheless suggested possible mechanisms by which long-term use of the drugs could trigger dementia or kidney problems. A reduction in vitamin B12, for example, might leave the brain more vulnerable to damage, says Britta Haenisch, an author of the JAMA Neurology study and a neuropharmacologist at the Bonn campus of the German Center for Neurodegenerative Diseases. Last spring clinicians at the Houston Methodist Research Institute reported another plausible explanation for how PPIs might lead to these unexpected health issues: they picked up signs that the drugs act not only in the stomach but elsewhere in the body, too.

These discoveries leave patients and doctors alike wondering who should and should not use proton-pump inhibitors long term. “At this point, we don't have enough data to weigh one risk versus the other,” says Kyle Staller, a leading gastroenterologist at Massachusetts General Hospital. But he and others are feeling their way forward.

Proton Pumps

Some amount of acid is, of course, crucial for the stomach to break down food. Specialized cells that dot the stomach's inner lining pump out hydrogen ions, or protons, which, from a chemical point of view, are what make the stomach's juices so acidic. As the name implies, proton-pump inhibitors reduce acid in the stomach—and thus reflux into the esophagus—by shutting down many of these cellular pumps. The shutdown is permanent, but the drugs are not cures, because the cells replace lost pumps. Another popular class of drugs known as H2 blockers (Tagamet among them) also limit acid production but in a different, less powerful way. Antacids, such as Tums, neutralize stomach acids but are even less potent, useful only for occasional, mild discomfort.

The effectiveness of PPIs has fueled a huge surge in their use since their release in the 1980s. Today they are available both over the counter and by prescription, and Nexium remains one of the most prescribed medications in the world.

The studies reported in 2016 grew out of earlier hints that such chronic use could affect the brain and kidneys. One 2013 study in PLOS ONE, for instance, found that proton-pump inhibitors can enhance the production of beta-amyloid proteins, a hallmark of Alzheimer's. Three years later the JAMA Neurology study, which included 74,000 Germans older than 75, found that regular PPI users had a 44 percent higher risk of dementia than those not taking PPIs.

Similarly, worries about kidneys emerged from evidence that people with sudden renal damage were more likely to be taking PPIs. In one 2013 study in BMC Nephrology, for example, patients with a diagnosis of kidney disease were found to be twice as likely as the general population to have been prescribed a PPI. The 2016 study of PPIs and kidney disease, which followed 10,482 participants from the 1990s through 2011, showed that those who took the drug suffered a 20 to 50 percent higher risk of chronic kidney disease than those who did not. And anyone who took a double dose of PPIs every day had a much higher risk than study subjects who took a single dose.

The 2016 Houston Methodist study that suggests a new explanation for a link between PPIs and Alzheimer's or kidney problems looked at cells that were grown in culture. It showed that besides acting on cells in the stomach, the drugs also affect certain cells that normally line blood vessels.

As with many other cells in the body, those in blood vessel walls need to make acid so that they can break down and get rid of abnormal or damaged proteins. The cells safely store the acid in special internal compartments, which essentially serve as molecular garbage dumps. If, however, a cell's internal trash is not broken down—as occurs if acid levels are too low—bits of microscopic detritus start to pile up. A cell overflowing with its own garbage cannot function properly and quickly becomes damaged. “We actually showed these rubbish piles accumulating in the cells,” says John Cooke, a cardiovascular researcher at Houston Methodist and one of the study authors. The resulting problems can become particularly severe wherever many blood vessels are found—as is the case in the brain and kidneys. Indeed, some recent studies have also hinted at a possible connection between long-term use of PPIs and damage to another organ with lots of blood vessels, the heart.

Though reasonable, Cooke's conclusion cannot be considered proved. Proof would require more study of the effect of proton-pump inhibitors on the vasculature in animals or humans, as opposed to cell cultures. Researchers also need to explore other factors that could account for the link between PPIs and dementia, heart disease or kidney problems. After all, some of the most well-known risks for these conditions are smoking, obesity and a high-fat diet, which, as it happens, also increase the likelihood of acid reflux. In this case, use of drugs could be a marker for certain unhealthy habits—versus a new, additional cause for these conditions.

Decisions, Decisions

Without conclusive data, physicians and patients have to balance the need to prevent the ill effects of excess stomach acid and reflux with the desire to avoid potentially serious—if theoretical—side effects from long-term use of PPIs.

Many doctors worry that reports of potential side effects will scare away patients who have a real need for the medication. Some people with GERD, for example, suffer from such miserable heartburn without PPIs that they struggle with daily life. Untreated acid reflux also carries risks besides acute pain. Studies have shown that it may, over time, alter the lining of the esophagus in a way that increases the risk for a condition called Barrett's esophagus, which can, in turn, be a precursor to cancer. Reducing acid is thought to help reduce the risk. (It is also possible to get Barrett's esophagus or cancer without having had any reflux symptoms, however.)

Whenever one of Staller's patients at Mass General says he or she wants to stop taking a PPI, he likes to perform a simple test. He has the person stop taking the medication for a week and substitutes Tagamet or another H2 blocker. (Stopping a PPI cold turkey, without adding another drug, typically causes a rebound effect, pushing the stomach to produce even more acid than it otherwise would.) He also recommends cutting back on acidic and spicy food for the length of the test. Then he sees if the patient is still bothered by heartburn at the end of a week, especially during the day, when gravity should help prevent acid from rising up into the throat. The persistence of heartburn indicates the presence of a more severe problem, Staller says. And thus, the benefit of taking a daily PPI outweighs the risks in such cases.

The calculus, obviously, is different for everyone. For Vicki Scott Burns, a children's book author in Bolton, Mass., PPIs are “the lesser of two evils.” She says her quality of life is vastly better on the drugs. Others might reach an alternative conclusion. In the end, Staller and other health experts advise patients and their physicians to gather and evaluate as much information as possible before making a decision—and to be prepared to change course if new evidence comes to light.