Dozens of commonly prescribed and over-the-counter medications can cause diarrhea, but a handful of drug categories are responsible for most cases. Antibiotics are the most frequent culprit, followed by diabetes medications like metformin, acid-reducing drugs, magnesium-containing supplements, and pain relievers. Chemotherapy drugs carry the highest rates overall, with diarrhea affecting up to 80% of patients on certain regimens.
Antibiotics
Antibiotics are the single most common medication category linked to diarrhea. They work by killing bacteria, but they don’t distinguish between harmful bacteria and the beneficial bacteria living in your gut. When that microbial balance gets disrupted, the result is often loose or watery stools. Broad-spectrum antibiotics, the ones designed to target a wide range of bacteria, carry the highest risk because they do the most collateral damage to your gut flora.
Timing varies quite a bit. Mild cases can start within hours of your first dose or build over a few days. More serious antibiotic-associated diarrhea sometimes doesn’t show up until days or even two months after starting the medication, which means you might not immediately connect it to the drug.
The biggest concern with antibiotic-associated diarrhea is a bacterial infection called C. difficile, which can take hold once antibiotics have cleared out competing gut bacteria. C. difficile causes persistent, foul-smelling diarrhea and can become dangerous if untreated. It’s most common with broad-spectrum antibiotics, in older adults, and in people who’ve been hospitalized recently.
Metformin and Diabetes Medications
Metformin, the most widely prescribed drug for type 2 diabetes, causes diarrhea in roughly 13% of people who take it. That rate is about 2.4 times higher than what’s seen with a placebo, making it one of the most predictable side effects of the drug. Interestingly, a large meta-analysis found that neither the dose nor how long you’ve been taking metformin significantly changes your risk. Some people get diarrhea on a low dose; others tolerate high doses without trouble.
One thing that does make a difference is the formulation. The immediate-release version of metformin causes more bloating and diarrhea than the extended-release version. If gut problems are an issue, switching formulations is a common first step. For many people, symptoms also improve on their own after the first few weeks as the body adjusts.
Acid-Reducing Drugs (PPIs)
Proton pump inhibitors, sold under names like omeprazole, lansoprazole, and esomeprazole, reduce stomach acid and are among the most widely used medications in the world. They can contribute to diarrhea in two ways. First, by lowering stomach acid, they remove one of your body’s natural defenses against swallowed bacteria, allowing more microbes to reach the intestines. Second, long-term use significantly raises the risk of C. difficile infection.
Multiple large analyses, pooling data from over 300,000 patients, have found that PPI use increases the odds of developing a C. difficile infection by about 70%. People who already have a history of C. difficile face an even steeper risk: one study found a 42% increase in recurrent infections among PPI users. This is particularly relevant for people taking PPIs alongside antibiotics, since both drugs independently raise C. difficile risk.
NSAIDs and Pain Relievers
Nonsteroidal anti-inflammatory drugs like ibuprofen, naproxen, and aspirin are best known for causing stomach ulcers and heartburn, but they can also trigger diarrhea. The mechanism involves prostaglandins, protective compounds that help regulate fluid balance and blood flow in the intestinal lining. NSAIDs block prostaglandin production throughout the body, and in the gut, this can disrupt normal fluid absorption.
For most common NSAIDs, the reported rate of diarrhea in clinical trials is around 1% or less, not dramatically different from a sugar pill. One notable exception is meclofenamate, a less commonly prescribed NSAID, which has caused diarrhea in up to 30% of patients in clinical trials. If you’re taking a standard over-the-counter NSAID like ibuprofen and experiencing persistent diarrhea, the drug could be contributing, but other causes are worth investigating too.
Magnesium Supplements
Magnesium is one of the most popular supplements on the market, and its laxative effect is well established. In fact, diarrhea was the specific side effect that led researchers to set the tolerable upper intake level for supplemental magnesium at 350 mg per day for adults. Above that threshold, unabsorbed magnesium draws water into the intestines through osmosis, loosening stools.
Your actual tolerance depends on the form of magnesium and how you take it. Magnesium oxide and magnesium citrate are more likely to cause gut issues than forms like magnesium glycinate, which are absorbed more efficiently and leave less unabsorbed mineral in the intestines. Taking your supplement with food and splitting the dose across the day also helps. This osmotic effect is the same principle behind magnesium-based laxatives like milk of magnesia, just at a higher dose.
Chemotherapy Drugs
Chemotherapy causes some of the most severe medication-related diarrhea. Rates depend heavily on the specific drug and dosing schedule, but certain regimens cause diarrhea in 50% to 80% of patients, with a significant portion reaching severe grades that require medical intervention.
Two of the worst offenders are fluorouracil (especially when given as a rapid injection rather than a slow infusion) and irinotecan. Severe diarrhea occurs in about 32% of patients receiving irinotecan and up to 37% of those on bolus fluorouracil with certain companion drugs. Irinotecan also causes a distinctive early-onset diarrhea within 24 hours of treatment, separate from the later diarrhea that develops days afterward. Diarrhea-associated mortality in clinical trials of these drugs has been reported as high as 3.5%, which is why oncology teams monitor bowel symptoms closely and have specific protocols for managing them.
Genetics also play a role. Patients with a specific variation in a liver enzyme that processes irinotecan experience severe diarrhea at a rate of 70%, compared to 15% in patients without the variation. Some cancer centers now test for this before starting treatment.
Other Common Offenders
Several other medication categories frequently cause diarrhea:
- SSRIs and other antidepressants. Serotonin, the brain chemical these drugs increase, also plays a major role in gut motility. Most of the body’s serotonin is actually produced in the intestines, so boosting its levels can speed up digestion and cause loose stools, especially in the first few weeks.
- Laxatives. Overuse or even standard use of stimulant laxatives and stool softeners can overshoot the mark. Osmotic laxatives containing polyethylene glycol or lactulose are dose-dependent, so even small adjustments can tip the balance.
- Colchicine. Used for gout flares, colchicine is notorious for causing diarrhea at doses very close to its therapeutic range. Diarrhea is often the first sign that the dose is too high.
- Heart and blood pressure medications. Certain ACE inhibitors, beta-blockers, and the heart rhythm drug digoxin can all cause diarrhea, though rates are generally low.
Why Some People Are More Affected
Two people can take the same medication at the same dose and have completely different gut reactions. Part of this comes down to the composition of your gut microbiome, which varies enormously from person to person. People with a less diverse bacterial population may be more vulnerable to disruption. Age matters too: older adults have less resilient gut flora and are more susceptible to complications like C. difficile.
Taking multiple diarrhea-causing medications at once compounds the risk. Someone on an antibiotic and a PPI simultaneously, for example, faces a higher chance of gut problems than someone on either drug alone. Pre-existing conditions like irritable bowel syndrome or inflammatory bowel disease also lower the threshold at which a medication triggers symptoms.
Warning Signs to Take Seriously
Most medication-related diarrhea is uncomfortable but not dangerous. It resolves after the drug is stopped or the body adjusts. However, certain symptoms signal something more serious: a fever of 102°F or higher, blood or pus in the stool, black or tarry stools, signs of dehydration (dizziness, dark urine, dry mouth), or severe abdominal pain. In adults, diarrhea lasting more than two days without improvement also warrants attention. For children, that window is 24 hours.