Since their introduction to the market in 1989, proton pump inhibitors (PPIs) have quickly become one of the most commonly prescribed medications in the world, with more than 100 million PPI prescriptions written each year in the United States alone. (14) The conditions that these drugs treat are both varied and common; including a wide range of gastrointestinal (GI) disorders such as peptic ulcers and gastroesophageal reflux disease (GERD). (5) It’s estimated that more than 25% of the US population is affected by acid-related conditions such as GERD. (14) And when you add in people with gastric ulcers, Helicobacter pylori (H. pylori) infection, and the extensive off-label chronic use, the number of users expands exponentially. (7)
These drugs are only indicated for short-term use; however, beginning in 2003, many of these medications became available over-the-counter (OTC), making chronic, long-term use more prevalent. (5) With long-term use comes potentially increased risks and side effects.
How do proton pump inhibitors work?
The risks and side effects of these medications are directly linked to how proton pump inhibitors work. The stomach secretes acidic fluid as low as pH 2 to help sterilize bacteria in foods and to assist with the digestion and absorption of various nutritional factors such as vitamin B12, calcium, iron, and protein. (8) There are mechanisms in place to help protect GI mucosa from gastric secretion-induced damage. However, if these protective mechanisms are overcome by acid secretion, the mucosa is damaged and irritated, causing uncomfortable and potentially dangerous symptoms. That’s when PPIs are employed because these drugs reduce the amount of acid produced by the glands that line the stomach. (12)
PPIs are available either with or without a prescription. Following is a proton pump inhibitors list of the most common brands that are presently being marketed in the United States: (12)
- Dexlansoprazole (Dexilant) available OTC
- Esomeprazole (Nexium) available OTC
- Lansoprazole (Prevacid) available OTC
- Omeprazole (Prilosec) available OTC
- Pantoprazole (Protonix) available with a prescription
- Rabeprazole (AcipHex) available with a prescription
- Zegerid (omeprazole with sodium bicarbonate) available OTC
Long-term use of PPIs can increase the risk of complications, as well as side effects and nutrient deficiencies. Perhaps most troublesome is the increased risk of dementia/Alzheimer’s, gastric cancer, and kidney and liver disease. (8)
Specific to dementia and Alzheimer’s disease, preliminary research indicates that PPIs may interfere with an important scavenger enzyme that can lead to an accumulation of beta-amyloid, which is a key factor in the development of Alzheimer’s. (7)
PPI use is also linked to both acute kidney injury and chronic kidney disease. In one study, PPI users had a 50% chance of developing chronic kidney disease than people who did not use PPIs, and there was a 64% increased risk of acute kidney injury. (9)
PPIs are also associated with both premalignant changes and lesions in the stomach, as well as increased risk of gastric cancer. (4) But it’s not just the stomach that is negatively impacted by these medications, as there is a downstream effect of the hypoacidity that can also affect the liver. Research demonstrates a direct link between PPI use and increased risk of cirrhosis and liver cancer. (4)
In addition to disease complication risks, PPI use can lead to a variety of different side effects, including:
- Bone fracture
- Changes in the gut microbiome
- GI infection (specifically H. pylori)
- Small intestinal bacterial overgrowth (8)
A common and concerning significant side effect of long-term PPI use is nutrient deficiencies and impaired nutrient absorption.
Research is clear that PPI use can cause vitamin B12 and magnesium deficiencies. In 2011, the US Food and Drug Administration issued a safety warning to those taking PPIs regarding impaired magnesium absorption and the development of hypomagnesemia, recommending close monitoring of magnesium levels. (11)
Regarding vitamin B12, gastric acid is needed to remove B12 from dietary proteins so this important vitamin can be absorbed. When gastric acid is reduced, vitamin B12 deficiency can result and is common among people taking PPIs, with one study showing a 65% increased risk of vitamin B12 deficiency. (11) Just as with magnesium, patients taking PPIs should have their vitamin B12 levels consistently monitored.
Fortunately, there are natural alternatives available for these common GI disorders.
Natural digestive support
GERD occurs when the muscle at the end of the esophagus doesn’t close properly and contents from the stomach leak back into the esophagus, causing irritation and uncomfortable symptoms such as heartburn. (13) While we often think of melatonin as a sleep supplement, promising research shows that it can also help with GERD and peptic ulcer disease. While there have only been a few human studies, preliminary research shows that melatonin might be as effective as omeprazole. (6) Although more research is needed to confirm these effects, melatonin has a much better safety profile than PPIs so it may be worth considering.
Many herbs can be used to reduce symptoms of GERD, including slippery elm, marshmallow leaf and root, and aloe vera leaf gel. (15)
Regarding ulcers, deglycyrrhizinated licorice (DGL) may be clinically valuable. While more human clinical trials are needed, a 2014 study found that DGL was as effective as bismuth in eradicating H. pylori, a key cause of ulcers, when provided with a traditional H. pylori eradication regimen. (10)
Other GI issues, specifically irritable bowel syndrome (IBS), can be relieved by using enteric-coated peppermint oil. PPIs are commonly used in patients with IBS because nearly 40% of those patients also have GERD. (2) A 2019 meta-analysis featuring 12 randomized trials found that peppermint oil was safe and effective at relieving IBS pain and other symptoms. (1) Research shows that peppermint oil can decrease esophageal and stomach spasms, ease indigestion, and encourage stomach and intestinal emptying. (3)
- Alammar, N., Wang, L. Saberi, B., Nanavati, J., Holtmann, G., Shinohara, R. T., & Mullin, G. E. (2019). The impact of peppermint oil on the irritable bowel syndrome: a meta-analysis of the pooled clinical data. BMC Complementary Medicine and Therapies, 19, 21. https://bmccomplementmedtherapies.biomedcentral.com/articles/10.1186/s12906-018-2409-0
- Chey, W. D., & Spiegel, B. (2010). Proton pump inhibitors, irritable bowel syndrome, and small intestinal bacterial overgrowth: coincidence or Newton revisited? Clinical Gastroenterology and Hepatology, 8(6), 480-482. https://www.cghjournal.org/article/S1542-3565(10)00247-8/fulltext
- Chumpitazi, B. P., Kearns, G., & Shulman, R. J. (2018). Review article: the physiologic effects and safety of peppermint oil and its efficacy in irritable bowel syndrome and other functional disorders. Aliment Pharmacol Ther, 47(6), 738-752. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814329/
- Fossmark, R., Martinsen, T. C., & Waldum, H. L. (2019). Adverse effects of proton pump inhibitors—evidence and plausibility. Int J Mol Sci, 20(20), 5203. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829383/
- Hayes, K. N., Nakhla, N. R., & Tadrous, M. (2019). Further evidence to monitor long-term proton pump inhibitor use. JAMA Netw Open, 2(11). https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2755847
- Hume, A. (2016). Melatonin eases GERD symptoms, studies show. Pharmacy Today, 22(8), 31. https://www.pharmacytoday.org/article/S1042-0991(16)30687-9/fulltext
- Jaynes, M., & Kumar, A. B. (2019). The risks of long-term use of proton pump inhibitors: a critical review. Ther Adv Drug Saf, 10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463334/
- Kinoshita, Y., Ishimura, N., & Ishihara, S. (2018). Advantages and disadvantages of long-term proton pump inhibitor use. J Neurogastroenterol Motil, 24(2):182-196. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885718/
- Lazarus B., Chen, Y., Wilson, F. P., Sang, Y., Chang, A. R., Coresh, J., & Grams, M. E. (2016). Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med, 176(2), 238-46. https://pubmed.ncbi.nlm.nih.gov/26752337/
- Momeni, A., Rahimian, G, & Kheiri, S. (2014). Effect of licorice versus bismuth on eradication of Helicobacter pylori in patients with peptic ulcer disease. Pharmacognosy Res, 6(4), 341-344. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4166824/
- Nehra, A. K., Alexander, J. A., Loftus, C. G., & Nehra, V. (2018). Proton pump inhibitors: review of emerging concerns. Mayo Clinic Proceedings, 93(2), 240-246. https://www.mayoclinicproceedings.org/article/S0025-6196(17)30841-8/fulltext
- NIH US National Library of Medicine. (2021 May 4). Medline Plus Proton Pump Inhibitors. https://medlineplus.gov/ency/patientinstructions/000381.htm
- NIH. (2021, May 17). Medline Plus GERD. https://medlineplus.gov/gerd.html
- Ren, D. (2019). Appropriate use and stewardship of proton-pump inhibitors. US Pharmacist, 44(12), 25-31. https://www.uspharmacist.com/article/appropriate-use-and-stewardship-of-protonpump-inhibitors
Yarnell, E., & Abascal, K. (2010). Herbs for gastroesophageal reflux disease. Alternative and Complementary Therapies, 16(6). https://www.liebertpub.com/doi/10.1089/act.2010.16611