Most of George Grossberg’s patients have lists of medications as long as his arm. So it takes the geriatric psychiatrist no small amount of time to go through those lists when he evaluates new patients in his clinic at Saint Louis University. One type of medication that regularly pops up: proton pump inhibitors (PPIs).
PPIs, which are used to treat persistent acid reflux or GERD (gastroesophageal reflux disease) — a condition affecting about one in five American adults, according to the National Institutes of Health — are frequently found on “most-used medication” lists. The six PPIs currently approved by the FDA are widely prescribed, and many are also available over the counter.
Most importantly, while many people find themselves continuously refilling prescriptions for PPIs, these drugs were never intended — nor studied — for long-term use.
The FDA’s recommended duration of treatment, typically ranging from 10 days to 12 weeks depending on the condition, is based on clinical trials that evaluated the drugs’ safety and effectiveness — none of which studied PPI use beyond 12 months. If symptoms persist or recur after an initial course, the FDA leaves room for additional short-term use but offers limited specifics, advising that decisions be made under a physician’s supervision. (For instance, the FDA-approved labeling for Prilosec (omeprazole) states that if symptoms of GERD return, additional four- to eight-week courses can be considered with a healthcare provider’s oversight.)
This limited guidance is part of what concerns Dr. Grossberg. While PPIs were never intended for indefinite use, patients are often left in a gray area — uncertain whether they should remain on the medication, transition to another treatment, or stop altogether.
Recent headlines linking PPIs to dementia have made Dr. Grossberg even more cautious. “There’s reason to believe these medications could negatively impact the brain,” he says.
An October 2023 study in the journal Neurology, which found a 33% increase in dementia risk for older adults who used PPIs for more than 4.4 years, was especially alarming to him. But as Dr. Grossberg found himself digging into the literature, he also uncovered analyses indicating no links between PPIs and dementia. Different studies, he realized, used different methodologies and statistical analyses, making it hard to come to a definitive conclusion. For the geriatric psychiatrist, it’s a huge conundrum. And he’s not alone.
What Are PPIs and How Do They Work?
The hydrochloric acid that exists naturally in everyone’s stomach is highly corrosive, with an average pH of around 2. Because hydrochloric acid is essential for digestion — breaking down food into small molecules that the body can use — the stomach has evolved ways to handle it.
A thick layer of mucus helps protect vulnerable stomach cells, and the lower esophageal sphincter (a ring-shaped muscle at the top of the stomach) acts as a one-way valve to keep acid in the stomach and away from the esophagus, the tube that connects the mouth to the stomach.
But the sphincter isn’t perfect, and occasionally, stomach acid seeps above it and into the esophagus. This can lead to heartburn, a painful, burning feeling most people experience now and then. Occasional heartburn, when it happens infrequently, typically doesn’t require more than standard over-the-counter treatment.
For more than 50 million Americans, however, this acid reflux occurs constantly.
Symptoms of GERD, which include burning feelings in the stomach or chest, regurgitation, and shortness of breath, aren’t just uncomfortable and annoying. Regular exposure to stomach acid damages the delicate tissues of the esophagus. Over time, this can lead to a condition called Barrett’s esophagus, a known risk factor for esophageal cancer.
In 1989, omeprazole — the first prescription proton pump inhibitor (PPI) — was introduced to the U.S. market by a Swedish pharmaceutical company under Astra AB (now AstraZeneca). This marked the arrival of a new class of medication for treating GERD. PPIs work by blocking the action of proton pumps, specialized enzymes in the stomach that produce its highly acidic environment.
PPI medications don’t eliminate all stomach acid, but rather prevent the production of excess acid. Reduced acid also reduces or eliminates symptoms of GERD and allows the esophagus time to repair and heal itself.
“From my point of view, proton pump inhibitors would be the only treatment of choice if there are signs of GERD,” says Babu Mohan, M.D., an Orlando-area gastroenterologist and member of the American Gastroenterological Association. “To help with the healing process, acid has to be completely suppressed.”
The common side effects (which generally means about 1 out of 100 people are likely to experience them) of short-term (several weeks or months) PPI usage tend to be mild, including nausea, diarrhea, constipation, and headaches.
For individuals who use PPIs for years, the side effects can become more serious, including an increased risk of kidney disease, liver disease, bone fractures from osteoporosis, gastrointestinal infections, and nutrient deficiencies.
Because GERD is such a common condition, as soon as PPIs hit the market, millions of people began turning to them to treat chronic acid reflux. However, as these drugs received a real-world test, patients started reporting side effects and drug interactions that weren’t noted in the initial trials.
B12 Deficiency, Dementia and PPIs: The Struggle To Understand the Connection
One of the earliest long-term side effects of PPIs to be discovered after the drugs were approved was an association with vitamin B12 deficiency. B12 deficiency is common in older adults, as is GERD. What’s more, the B12 we get from our diets is not immediately usable by our bodies — only after stomach acid, which PPIs suppress, snips off a small chemical appendage can cells absorb and utilize it.
Even though several early studies found conflicting results, a 2013 study in the Journal of the American Medical Association showed that people prescribed PPIs for at least two years had a 1.65 times higher risk of being diagnosed with a B12 deficiency. Users of another type of stomach acid reducer, called histamine 2 receptor antagonists (H2RAs), such as famotidine (Pepcid) or cimetidine (Tagamet), also showed an increased risk of vitamin B12 deficiency. (H2RAs are available both over-the-counter and by prescription, though are considered less effective at treating severe GERD.)
One especially concerning symptom of B12 deficiency is cognitive difficulty. Severe lack of vitamin B12 can lead to depression, paranoia, memory loss, and other neuropsychiatric symptoms. Theorizing that PPIs may be connected to reduced B12, a German research team set out to uncover if PPIs were also directly linked to cognitive issues.
In 2014, the scientists analyzed data from a long-term community study of 3,327 adults aged 75 and older. Among them, 421 people used PPIs at some point during the study, and 2,312 did not. During the study, 50 PPI users developed dementia, compared to 165 non-users. Overall, their research indicated that people who had PPI prescriptions were 1.4 times more likely to be diagnosed with dementia during the study.
However, the study design itself limited what scientists could conclude from the findings. The researchers didn’t have data on how frequently the patients took PPIs, on potential biological mechanisms connecting the drugs to cognitive issues, or which study participants were already living with B12 deficiencies. Nor could the researchers determine whether the dementia was linked to a B12 deficiency that predated PPI use — or whether the PPI use itself contributed to a deficiency that then affected cognition.
As a purely observational study, the researchers could document only an association between PPIs and dementia, not whether PPI use caused dementia.
The real challenge is determining whether PPI use, B12 deficiency and dementia are directly linked or just coincidental, says Jacob Kurlander, M.D, a gastroenterologist at the University of Michigan. “It’s easy to find associations,” he notes, “but more difficult to prove causation.”
Another Link to Dementia: PPIs May Enhance Beta Amyloids
In December 2024, researchers at the German Center for Neurodegenerative Diseases reported an association between regular use of proton pump inhibitors (PPIs) for at least 3 years and impairments in both cognitive and working memory. Long-term PPI users also showed disruptions in the brain’s white matter — the fatty tissue known as myelin that insulates nerve fibers and is critical for fast, efficient communication between neurons.
This study is the latest in a growing body of research stretching back more than a decade theorizing that instead of triggering a deficiency that could create the symptoms of dementia, PPIs might increase dementia directly.
One proposed mechanism involves the enzymes our cells use to break down old and dysfunctional proteins — such as the clumps of amyloid beta and tau that accumulate in the neurons of people with Alzheimer’s disease. These enzymes share structural similarities with proton pumps, raising the concern that PPIs could interfere with this vital cellular recycling process.
This theory was actually explored in a study as early as 2013, when researchers found that the PPI lansoprazole enhanced the formation of certain types of amyloid beta proteins in both cultured human neurons and in mice. They also discovered that some PPIs can bind strongly to specific forms of the tau protein, potentially encouraging the formation of toxic, tau-containing neurofibrillary tangles associated with dementia.
In a follow-up to their 2014 observational study in Germany, the same team of researchers used data from a prospective cohort study of more than 73,000 older adults. By following individuals without a dementia diagnosis at baseline, researchers could more clearly understand potential causation in the association between PPIs and dementia. In this second study, published in JAMA Neurology, the German team also found that regular use of PPIs (defined as consistent PPI prescriptions over the study interval) increased the risk of dementia 1.44 times.
In another large-scale study, epidemiologists from Copenhagen University Hospital followed 1.98 million Danes between the ages of 60 and 75 for an average of 10 years. Of those who developed dementia, 21.4% had a PPI prescription, but only 18.4% of those who didn’t develop dementia used PPIs. This increase in risk was statistically significant for those who redeemed at least two PPI prescriptions, the researchers concluded.
When a group of Chinese scientists analyzed data from more than 500,000 individuals in the UK Biobank in 2022, they too found a significant association between the daily use of PPIs for at least 4 weeks and dementia diagnosis
In October 2023, researchers from the University of Minnesota followed 5,712 dementia-free older adults (with an average age of 75) for 5.5 years. When they compared those individuals newly diagnosed with dementia during the study to those not diagnosed, the researchers found that those who took PPIs for at least 4.5 years during their lifetime had a 33% increased risk of developing dementia. The researchers found no association when PPIs were taken for short time periods, according to results published in Neurology.
Some Studies Find No Link Between PPIs and Cognitive Risk
But as Dr. Grossberg discovered, the confounding issue when it comes to PPIs and their association with cognitive issues, is that for every study that finds an association, there is another study that doesn’t.
In 2024, Scientists from Sichuan University analyzed data from the UK Biobank and the FinnGen database (a large-scale Finnish research project detailing genetic data). They initially found that certain PPIs, such as lansoprazole and pantoprazole, might increase dementia risk. However, after adjusting for multiple comparisons, these effects disappeared. In their study, the researchers concluded that restricting clinically necessary PPI prescriptions based on potential cognitive risks would be unwarranted.
Another large-scale study, published in 2023, analyzed data from the ASPREE trial, which enrolled participants aged 65+ between 2010 and 2014. Because it tracks outcomes over many years, this older dataset offered researchers valuable insight into the long-term effects of medication use. When any use of PPI and H2RA medications among the nearly 19,000 study participants were evaluated, the results showed no links between dementia diagnoses, cognitive impairment, or changes in cognition during the study.
Other meta-analyses, in which researchers compiled and analyzed data from numerous existing studies, also found no association between PPI use and dementia.
Pre-Existing Conditions and Differing Demographics: The Factors That Contribute to Such Wide Study Variability
Stefania Forner, Ph.D., director of Medical and Scientific Relations at the Alzheimer’s Association, points out that the evidence is likely inconclusive due to the fact that many of these studies have different demographics and patterns of long-term PPI use.
Another potential factor? Patients on PPIs are more likely to have GERD, but they’re also more likely to have a host of other conditions, including cardiovascular and kidney diseases, says Dr. Kurlander.
“It takes a really clever study design to tease these things out,” he says.
Because of these limitations, both the FDA and the Centers for Medicare and Medicaid Services advise using PPIs at the lowest effective dose for the shortest possible duration. This recommendation was outlined in an October 2015 fact sheet.
Despite these guidelines, people with the most severe forms of GERD may have to take PPIs “indefinitely,’ notes Dr. Mohan. A 2022 guideline from the American College of Gastroenterology for the treatment of GERD recommends PPI treatment over H2RAs and other therapies. Still, those with less severe disease should be counseled to lower their dosage or stop taking the medications completely once the acid damage has healed, he continues.
The problem, says Dr. Grossberg, is that this isn’t always what happens. Many of his patients have less severe forms of GERD, but their physicians continue prescribing PPIs indefinitely. “Some people are on these for years, when they don’t need to be on anything,” he says.
Because PPIs haven’t been studied in clinical trials lasting beyond 12 months, yet are frequently taken for far longer (even in research settings), it’s perhaps unsurprising that potential side effects — including cognitive impairment — have remained difficult to conclusively pin down.
Ongoing Questions About PPIs: Weighing the Evidence and Your Options
While these kinds of mixed findings in the medical literature can be deeply frustrating for both physicians and patients, such ambiguity is far from rare in medicine; in fact, it’s more often the rule than the exception, notes Joseph Ross, M.D., MHS, a professor of Medicine and Public Health at the Yale-New Haven Hospital.
It’s also important to note that conflicting findings do not inherently indicate shoddy research. Different study designs, different data sets, different analyses — all of these factors can lead to disparate results. As it so often does, making an informed decision around PPI use depends on a discussion of risks and benefits with your physician.
“We in medicine don’t always do a very good job of helping people truly understand not just the benefits themselves, but the likelihood of benefits” for a specific individual, he says. It’s much harder to quantify a patient’s individual experience with a medication and use these to make broad recommendations.
To Dr. Mohan, PPIs are clearly indicated for patients with severe esophageal damage due to GERD.
“If you have a pre-cancerous condition, I tell my patients the benefits actually outweigh the risks. Because why would you want to have cancer in your food pipe?” he says. But he also points out that patients may be able to titrate their prescription dosage down after the inflammation clears up, often after just several months of treatment.
What Causes GERD? And Alternatives to PPIs
Dr. Mohan says that the causes of GERD are varied. Perhaps due age-related physiological changes, the risk of GERD increases as people get older, which is one reason physicians like Dr. Grossberg see so many older adult patients taking PPIs.
Other factors, such as smoking, obesity, pregnancy, alcohol and tobacco use, and anatomical abnormalities such as hernias, can also increase the risk of GERD.
Addressing recurring symptoms with a health provider before they become chronic and require lifelong treatment is an essential move, says Dr. Mohan.
For individuals with less severe disease, or with more occasional heartburn, plenty of non-PPI options exist.
Other classes of medications, such as H2RAs and over-the-counter remedies such as calcium carbonate (like Tums and Rolaids), may also help alleviate symptoms with fewer long-term issues.
These drugs have different ways of relieving GERD symptoms. Calcium carbonate, for example, raises the pH of stomach acid so it’s less corrosive. H2RAs, on the other hand, decrease stomach acid production by binding to histamine receptors in the stomach. These drugs act quickly (unlike PPIs, which require one to three days to reach full efficacy), but people are more likely to develop tolerance to their effects than with PPIs.
Dr. Grossberg also points to numerous effective, non-pharmacologic treatments such as changing the types, timing, and frequency of meals, as well as using extra pillows to elevate the head and neck during sleep.
Interestingly, a small 2017 study explored whether a Mediterranean diet combined with alkaline water could reduce symptoms of laryngopharyngeal reflux (LPR), a type of acid reflux that affects the throat and voice box, as effectively as PPIs. Although the study didn’t focus on GERD specifically, researchers found that 63% of participants in the diet and water group showed clinically meaningful improvement; slightly more than the 54% in the PPI group.
Outside of trying non-pharmacologic treatments for GERD, Dr. Grossberg also recommends that patients and physicians reevaluate whether they need to continue taking certain prescriptions. Often, doctors default to renewing a prescription without asking whether it’s still needed, notes Dr. Grossberg, and patients are the ones who have to initiate these conversations.
“In our healthcare system, especially with older adults, people end up on more and more medications,” says Dr. Grossberg. “Deprescribing is not part of the picture, so things are continued almost indefinitely.”
If you think you or a loved one could benefit from deprescribing — the careful process of reducing or stopping medications that may no longer be helpful — consider making it a priority conversation at your next appointment. This is especially important if you believe you are taking a medication, such as a PPI, for longer than the FDA-approved duration of use.
