The Food and Drug Administration and numerous studies have demonstrated that long-term use of proton pump inhibitors (PPIs) can be associated with many adverse effects, including increased risk of fracture, low magnesium, low vitamin B12, gastrointestinal infections, and impaired kidney function. However, sometimes a health professional may determine that a patient must remain on PPIs long-term, perhaps indefinitely. Integrative clinicians can support patient well-being through lifestyle and diet and by supporting micronutrient status.

The following protocol should be offered for eight weeks, then re-evaluate the patient’s symptoms.

*Occasional heartburn or indigestion.

Pure Encapsulations O.N.E Multivitamin

Take 1 capsule per day

Designs for Health Magnesium Malate

Take 2 capsules at bedtime

Biotics Research Saccharomyces boulardii

Take 1 capsule twice daily

Pure Encapsulations Digestive Enzymes Ultra 

Take 1 to 2 capsules with the main meal of the day

Integrative Therapeutics Betaine HCl 

Titrate with a protein-containing main meal of the day (see Clinician Directed Protocol of Betaine HCl below) 

Clinician Directed Protocol of Betaine HCl

Many integrative and functional medicine practitioners use the following protocol to determine if an individual has low stomach acid:

  • Have the patient take one capsule/tablet of betaine HCl (500–700 mg) immediately before eating a protein-containing meal. Have the patient watch for any feelings of discomfort (e.g., heartburn, stomach pain, back pain). If they feel any burning or pain, instruct them to mix 1 tsp of baking soda in a glass of water and drink it to neutralize the acid. If the patient experiences discomfort with one capsule/tablet, discontinue the trial altogether.
  • After two days, if the patient hasn’t experienced any discomfort, increase to two capsules/tablets immediately before eating a protein-containing meal. Again, instruct them to watch for any feelings of discomfort. If they feel any burning or pain, neutralize the acid with baking soda and then bring them back down to one tablet/capsule before the main protein-containing meal of the day.
  • After two days at this dose, if the patient still hasn’t felt any discomfort, increase to three capsules/tablets immediately before eating a protein-containing meal. Again, have them watch for any feelings of discomfort. If they experience any discomfort, have them neutralize the acid with baking soda and back the dose down to two capsules/tablets.
  • In my experience, most people experience discomfort at a dose of 2,000–3,000 mg. Do not exceed 3,000 mg. It is absolutely critical to instruct the patient to only take betaine HCl when they eat a protein-rich meal. If it is a smaller meal, dosing should be reduced, or the product should NOT be taken.

Supplemental Material

  • Monitor B12 — Studies show that long-term PPI use can lower serum B12 levels, (10) especially in older patients. Monitor annually by testing serum B12 or methylmalonic acid. If deficient, treat appropriately. Supplement with 250–500 mcg vitamin B12 per day.
  • Monitor magnesium — The FDA recommends that health care professionals check magnesium prior to prescribing PPI and periodically in those who must take them long-term. (4) There is debate whether RBC magnesium is superior to serum. Many magnesium researchers suggest a lower reference limit of serum magnesium should be 0.85 mmol/L (2.07 mg/dL), especially for patients with diabetes. (14) Supplement with 300–400 mg per day (or higher, based upon patient’s age and renal function).
  • Monitor vitamin D — The FDA has reported that PPIs increase the risk of osteoporotic fracture. (3) Clinicians should counsel patients about calcium intake and check serum 25(OH)D to maintain a level of 30 ng/mL or above. Correct deficiency (50,000 IU once per week for 8–10 weeks and then recheck level). Maintenance: 2000 IU vitamin D3 per day.
  • Monitor ferritin — Long-term PPI use can lower iron levels and increase the risk for iron deficiency anemia. (1) Consider checking ferritin annually. A cutoff of ≤ 30 ng/mL is highly specific for iron deficiency anemia. Treat appropriately.
  • Monitor kidney function — Studies show that PPIs can cause both acute and chronic kidney deterioration. (11) Therefore, clinicians should consider checking serum creatinine or urinalysis annually.
  • Counsel patients about difficile risk — The FDA instructs patients to seek immediate care if they take a PPI and develop diarrhea that does not improve. (5) There is evidence that specific probiotic strains reduce the risk of antibiotic-associated diarrhea (C. diff) by maintaining a healthy gut microbiota. (8)
  • Consider SIBO — studies show that PPIs modestly increase the risk for SIBO. There are home hydrogen/methane breath tests available via Metsol or Genova Diagnostics. Consider probiotics to support healthy gut microbiota. (6)
  • Healing Heartburn Naturally: A Guide to Managing Acid Reflux and Restoring Gut Health, by Tieraona Low Dog, MD, is a great resource for practitioners and patients. This eBook is completely referenced and has evidence-based recommendations for managing heartburn, tapering protocols for weaning off PPIs, and strategies for supporting those who must take long-term PPI therapy.

Important Notes:

  • The supplement is betaine HCl. Betaine is a compound naturally found in beets, spinach, wheat bran, and other foods and is safe.
  • Do not confuse betaine HCl with betaine trimethylglycine (TMG). These are two very different compounds and are used for different purposes.
  • Betaine HCl must be taken in a tablet or capsule to avoid the HCl from coming into contact with the esophagus. Do not open a capsule and pour onto food or in liquid.
  • Betaine HCl is contraindicated in those with gastric or duodenal ulcers (now or in the past).
  • Remember to instruct the patient never to take this supplement on an empty stomach unless followed immediately by a protein-containing meal.


The Fullscript Integrative Medical Advisory team has developed or collected these protocols from practitioners and supplier partners to help health care practitioners make decisions when building treatment plans. By adding this protocol to your Fullscript template library, you understand and accept that the recommendations in the protocol are for initial guidance and may not be appropriate for every patient.

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  1. Boxer M. Iron deficiency anemia from iron malabsorption caused by proton pump inhibitors. eJHaem 2020; Sept. 1
  2. Cheng J, et al. Gastroesophageal Reflux Disease and Probiotics: A Systematic Review. Nutrients 2020 Jan; 12(1): 132.
  3. Food and Drug Administration. FDA Drug Safety Communication: Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. Accessed June 12, 2021.
  4. Food and Drug Administration. FDA Drug Safety Communication: Low magnesium levels can be associated with long-term use of Proton Pump Inhibitor drugs (PPIs). Accessed June 12, 2021
  5. Food and Drug Administration. FDA Drug Safety Communication: Clostridium difficile associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). Accessed June 12, 2021
  6. Garcia-Collinot G, et al. Effectiveness of Saccharomyces boulardii and Metronidazole for Small Intestinal Bacterial Overgrowth in Systemic Sclerosis. Dig Dis Sci 2020 Apr;65(4):1134-1143.
  7. Guilliams TG, et al. Meal-Time Supplementation with Betaine HCl for Functional Hypochlorhydria: What is the Evidence? Integ Med 2020 Feb; 19(1): 32–36.
  8. Guo Q, et al. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev 2019 Apr 30;4(4):CD004827.
  9. Hafiz RA, et al. The Risk of Community-Acquired Enteric Infection in Proton Pump Inhibitor Therapy: Systematic Review and Meta-analysis. Ann Pharmacother 2018 Jul;52(7):613-622.
  10. Jung SB, et al. Association between vitamin B12 deficiency and long-term use of acid-lowering agents: a systematic review and meta-analysis. Intern Med J 2015 Apr;45(4):409-16.
  11. Moledina DG, et al. Proton Pump Inhibitors and CKD. Journal of the American Society of Nephrology 2016 Oct: 27 (10) 2926-2928
  12. Su T, et al. Meta-analysis: proton pump inhibitors moderately increase the risk of small intestinal bacterial overgrowth. Journal of Gastroenterology 2018; 53: 27-36
  13. Sun J, et al. The use of anti-ulcer agents and the risk of chronic kidney disease: a meta-analysis. Int Urol Nephrol 2018 Oct;50(10):1835-1843.
  14. Workinger JL, et al. Challenges in the Diagnosis of Magnesium Status. Nutrients 2018 Sep; 10(9): 1202.
  15. Yago MR, et al. Gastric reacidification with betaine HCl in healthy volunteers with rabeprazole-induced hypochlorhydria. Mol Pharm 2013 Nov 4;10(11):4032-7.