What hidden side effects do common medications like PPIs and statins have?

Non-steroidal anti-inflammatory drugs are so ubiquitous that people forget they are real drugs with real consequences. Occasional use for acute pain is generally well tolerated. The problems emerge with regular, long-term use.

NSAIDs inhibit the COX enzymes that protect the stomach lining, and they can damage the gastrointestinal tract. In endoscopy studies lasting three months or more, ulcer rates ranged from 15% to 35% depending on the drug, and about 70% of patients develop NSAID enteropathy, which is associated with intestinal blood and protein loss. Serious outcomes such as bleeding are much rarer (usually less than 1 in 200 people taking them for a year), and the risk rises with age, a history of bleeding, H. pylori infection, and anticoagulant use. At over-the-counter doses, ibuprofen and diclofenac caused symptomatic gastrointestinal side effects comparable to placebo in the studies reviewed¹. Chronic NSAID use also places measurable strain on kidney function and has been associated with increased cardiovascular risk, including heart attack and stroke, particularly in patients with preexisting conditions.

The alternative conversation worth having: why is there chronic inflammation? Is it dietary? Is it a joint mechanics issue that physical therapy could address? The pain is a signal, and silencing it indefinitely with NSAIDs doesn't make the source go away.

Proton pump inhibitors (omeprazole, esomeprazole)

PPIs like Prilosec and Nexium were designed for short-term use — two to eight weeks for healing gastric ulcers or managing acute reflux. Yet millions of people take them for years, sometimes decades, often without anyone revisiting whether they're still necessary.

Long-term PPI use has been linked to significant nutrient malabsorption. A large case-control study in JAMA (25,956 patients with vitamin B12 deficiency and 184,199 without) found that a supply of PPIs lasting two or more years was associated with 65% higher odds of vitamin B12 deficiency (OR 1.65, 95% CI 1.58–1.73), and a two-year supply of H2 blockers with 25% higher odds (OR 1.25)². Because this is an association, it does not prove the drugs caused the deficiency. PPIs also reduce absorption of magnesium, calcium, and iron. The calcium malabsorption is particularly concerning — long-term PPI use is associated with increased fracture risk, especially hip fractures in older adults.

Perhaps most frustrating: stopping PPIs after prolonged use often triggers rebound acid hypersecretion, where the stomach produces more acid than it did before treatment. This creates a dependency cycle that makes discontinuation difficult without a gradual tapering plan.

Statins (atorvastatin, rosuvastatin, simvastatin)

Statins are among the most prescribed drugs in the world, and for people with established cardiovascular disease, the evidence for benefit is strong. For primary prevention in otherwise healthy people, the picture is more nuanced.

A well-documented side effect is muscle pain (myalgia); in meta-analyses of randomized trials, muscle side effects are more frequent with statins than with placebo. Researchers propose a mitochondrial mechanism: statins block the same metabolic pathway (the mevalonate pathway) that the body uses to produce coenzyme Q10, which is essential for mitochondrial energy production, and a review of the statin side-effect literature concluded that converging evidence supports a mitochondrial foundation for statin muscle side effects³. Supplementing with CoQ10 may help mitigate this effect (see our CoQ10 page for more).

Statins also carry a modest but real increase in the risk of developing type 2 diabetes, particularly in patients who are already prediabetic. This tradeoff — reducing cardiovascular risk while increasing metabolic risk — deserves a candid discussion between patient and doctor.

Selective serotonin reuptake inhibitors help many people with depression and anxiety, and for severe cases, they can be genuinely lifesaving. The issues arise in how they are prescribed, monitored, and — especially — discontinued.

A systematic review of 24 studies found that withdrawal effects from antidepressants occurred in a weighted average of 56% of people who stopped (range 27% to 86%), and that about 46% of those who experienced withdrawal endorsed the most extreme severity rating⁴. Seven of the ten studies that reported duration found that a significant proportion of people experienced withdrawal for more than two weeks, and withdrawal lasting several months was not uncommon, contrary to guidelines that call withdrawal self-limiting. Symptoms can include electrical "brain zaps," dizziness, insomnia, irritability, and a return of anxiety or depression that may be withdrawal rather than relapse — a distinction that is clinically critical but often missed.

Sexual side effects — reduced libido, difficulty with arousal or orgasm — affect a significant percentage of SSRI users, yet patients report that these effects are frequently minimized or omitted during the prescribing conversation.

Metformin

Metformin remains a first-line treatment for type 2 diabetes and is generally well tolerated. However, long-term use is clearly associated with vitamin B12 depletion, which can cause fatigue, neuropathy (nerve damage), and cognitive changes. Regular B12 monitoring is recommended but not always performed (see our B Vitamins page for details on why B12 matters).

The point is not to avoid these drugs

Every medication on this list helps real people with real conditions. The point is that "take this pill" should never be the end of the conversation — it should be the beginning of one. What are the risks? What is being depleted? How long should I take this? What else could I try? These are questions you have every right to ask.