Omeprazole Long-Term Side Effects: In-depth Risk Analysis (Dr. farahat).

Our content is not intended nor recommended as a substitute for medical advice by your doctor. Use for informational purposes only.

What You need to know:

  • Long-term omeprazole (and other PPIs) has been linked to many side effects.
  • However, Only a few of these side-effects are confirmed by research.
  • The remaining majority of the side effects are not yet confirmed.

Long-term omeprazole side effects:

  • Clostridiodies difficile infection.
  • Other infections and colonization of the intestine with multi-drug-resistant bacteria.
  • Magnesium deficiency.
  • Calcium deficiency (bone fractures).
  • Vitamin B 12 deficiency.
  • Iron deficiency.
  • Microscopic colitis.
  • Atrophic gastritis and hypergastrinemia.
  • Kidney disease (as acute interstitial nephritis).
  • Drug-induced lupus.
  • Other side effects with an unclear association: such as the risk of dementia, Covid-19 infection, pneumonia, and death. 

1. Clostridioides difficile infection (and others).

Long-term PPIs (as omeprazole) is associated with an increased risk of gut infections as:

Omeprazole is linked to both new and recurrent infections of clostridioides difficile infection. The organism is famous to cause a severe form of colon inflammation (pseudomembranous colitis).

Clostridioides difficile infection risk if very high with antibiotic use. However, studies showed that omeprazole increases the risk of clostridioides difficile infection regardless of the use of antibiotics (reference).

How much is the risk?

2017 meta-analysis of 56 studies showed that Omeprazole doubles the risk of C. difficile infection (CDI) with long-term use (reference).

The Relative Risk (RR) of C. difficile infection was 1.99. A Relative Risk (RR) of 1.99 means you are 1.99X more likely to have CDI with Omeprazole long-term use.

According to the same study, The risk is more when you take PPIs (as omeprazole) and antibiotics at the same time.

Also, another meta-analysis showed that omeprazole (and other acid-reducing drugs) increases the risk of intestinal colonization with multi-drug-resistant (MDR) organisms (reference).

Multi-drug-resistant organisms are difficult to treat when it flares up and causes disease.

The Relative Risk (RR) for Omeprazole-induced colonization of such organisms was 1.74% (You are 1.74 more likely to have MDR organisms in your colon with omeprazole use.

Symptoms of C. difficile infection:

  • Commonly, mild infection in the form of watery diarrhea (about 3-5 times per day) for two or more days with cramps.
  • The severe form is less common but carries significant risk.
  • Watery diarrhea 10-15 times a day.
  • Severe abdominal pain.
  • Rapid heartbeats.
  • Fever, which may become high-grade.
  • Bloody stool (bloody diarrhea).
  • Symptoms of dehydration as extreme thirst, fast heartbeats, dizziness, and too little urine.
  • loss of appetite and weight loss.

2. Deficiency of Magnesium and Calcium (bone fracture risk).


Long-term PPIs (as omeprazole) decrease the absorption of magnesium from your intestine.

The risk of hypomagnesemia with long-term Omeprazole was significantly higher. According to a meta-analysis (involving 109,798 patients), The relative risk was 1.43 (reference).

Symptoms of hypomagnesemia:

  • Tremors in hands.
  • Irritability.
  • Muscle weakness.
  • Apathy and confusion.
  • Tetany (spasms in the muscles of your limbs and face).
  • Convulsion (fits) in severe cases.
  • Irregular heartbeat (arrhythmias).

Hypocalcemia and fracture risk:

Long-term omeprazole may reduce the absorption of certain calcium supplements (as calcium carbonates).

However, Omeprazole doesn’t affect the absorption of calcium in other supplements (as calcium citrates) and calcium in dairy products (reference).

In a series of meta-analyses, The long-term PPIs (as omeprazole) slightly increased the risk of bone fractures. The relative risk (RR) was up to 1.56 (references).

The risk of bone fractures was more with:

  • Long-term use.
  • High doses (as Omeprazole 40 mg twice daily).

However, other studies failed to find an association between bone fractures and Long-term PPIs (omeprazole) (reference).

Overall, the link between calcium, bone fractures, and omeprazole is weak. The study results are controversial.

Obtaining enough calcium from dairy products seems to be a good strategy if you are on long-term omeprazole.

Ask your doctor about the need for calcium supplements if you’re on long-term omeprazole.

3. Vitamin B 12 and iron deficiency with long-term omeprazole.

Vitamin B12.

Long-term Omeprazole has been linked to decreased absorption of vitamin B12. Also, short-term (2-week) omeprazole treatment significantly decreased the amount of vitamin B 12 absorbed from3.2% to 0.9% (reference).

Regarding Long-term omeprazole, 2 or more years of omeprazole (or other PPIs) increases the risk of vitamin B 12 deficiency. The relative risk (RR) was 1.6 (reference).

Vitamin B 12 is vital for your blood and nervous system. Deficiency of vitamin B 12 leads to a diversity of symptoms such as:

  • Anemia: easy fatigue, shortness of breath, fast heartbeats, and pale skin.
  • Atrophy of your tongue lining (smooth tongue).
  • Constipation, diarrhea, gas, or loss of appetite.
  • Tingling, numbness, muscle weakness, and trouble walking.
  • vision problems (up to visual loss).
  • Behavioral, mood, or memory problems.

The good news?

Fortunately, Oral vitamin B supplementation is not affected by omeprazole use. Ask your doctor about the need for vitamin B 12 supplementation if you are on long-term PPI use.

Iron deficiency.

Omeprazole is an inhibitor of gastric acid secretion. Iron needs acid to be absorbed.

In theory, Omeprazole decreased the absorption of iron. However, the effect seems to be minimal and insignificant, it can affect both healthy and unhealthy individuals (reference).

The risk is more if you’re already anemic or have an iron deficiency (reference).

One study showed that long-term omeprazole (or any other acid-reducer) increases the risk of iron deficiency even in patients without risk factors for iron deficiency (reference).

MORE: Vitamin B12 101: Benefits, Sources causes of deficiency, & More. 

4. Microscopic colitis & omeprazole (a type of inflammatory bowel disease).

Microscopic colitis is a specific type of chronic colon inflammation. It causes severe watery diarrhea.

The term “microscopic” refers to the normal appearance of your colon via colonoscopy. The inflammation is only seen after microscopic examination of biopsy samples from the colon.

Microscopic colitis is classified as an Inflammatory bowel disease (together with Crohn’s and ulcerative colitis.

One study revealed that Long-term PPIs (such as omeprazole) increase the risk of microscopic colitis by 4.5 folds (reference).

Symptoms of microscopic colitis include:

  • Chronic watery diarrhea (non-bloody).
  • The onset of diarrhea is often insidious. It is about 4-9 motions per day.
  • Sometimes, urgency and fecal incontinence occur.
  • Abdominal cramps.
  • Nausea lost appetite.
  • Weight loss and dehydration.
  • Some patients suffer from painful joints, and eye affection.

MORE: Can omeprazole change your stool color? (yellow, black, green stools, and more).

5- Atrophic gastritis, and hypergastrinemia (small risk)

Atrophic gastritis is a type of chronic gastritis with atrophy of the stomach lining. Atrophic gastritis may result from long-term omeprazole use.

Omeprazole is thought to increase the gastrin hormone. High gastrin hormone (hypergastrinemia) results in hypertrophy of stomach glands and may induce a specific type of tumor called (neuroendocrine tumors).

However, the link between omeprazole, hypergastrinemia, and atrophic gastritis is weak.

For example, an 11-year omeprazole long-term treatment wasn’t associated with a higher risk of atrophic gastritis (reference).

6- Kidney disease.

Omeprazole was linked in the studies to various kidney diseases. Long-term PPIs (as omeprazole) are associated with kidney inflammation (acute interstitial nephritis), chronic kidney disease, and Kidney failure.

The most recognized side effect of omeprazole is acute interstitial nephritis (AIN). This type of inflammation appears to be an acute rather than chronic complication.

However, prolonged or recurrent use of omeprazole may lead to the recurrence of acute interstitial nephritis (reference).

An acute attack of omeprazole-induced AIN may pass unnoticed. However, long-term omeprazole may lead to kidney impairment or even kidney failure.

The link between long-term omeprazole and kindy disease is still not well-established. We need more studies to confirm the link.

7- Omeprazole-induced lupus.

PPI (including omeprazole) is associated with lupus, a chronic inflammatory disease that affects the skin and other body systems.

Most causes of lupus occurred with long-term use (weeks to years). Lupus usually improves within 4-12 weeks after the discontinuation of PPIs (reference).

8. Others (unclear associations).

The below diseases and conditions are controversial. Some studies linked them to long-term PPI Use (including omeprazole), while other studies found the opposite (reference):

  • Dementia in the elderly.
  • Pneumonia (chest infection).
  • Increased risk of Covid-19.
  • Increased risk of death.