Medications That Deplete Nutrients: Metformin, PPIs, Statins and More

Search for "medications that deplete nutrients" and you will find long charts claiming that almost every prescription drains a handful of vitamins, usually followed by a product to buy. A few of these depletions are real, important and written into the drugs' official US labels. Many others rest on small studies, blood-level changes that may not matter, or simply on being copied from chart to chart.

This guide sorts them by strength of evidence: metformin and vitamin B12, acid blockers and magnesium, statins and CoQ10, diuretics and potassium, seizure medicines, methotrexate, a new 2026 warning about levodopa and vitamin B6, and birth control. It also covers the cases where "replacing what the drug depletes" can backfire.

The evidence at a glance

We graded each pairing as strong (in the drug's US label with monitoring advice, in a guideline, or shown in a large trial or in consistent meta-analyses of randomized trials), moderate (consistent observational studies, which follow groups of people and can show a link but not prove cause, with uncertain clinical impact) or weak (small studies, blood-level shifts only, or mainly supplement-company charts).

Spironolactone, ACE inhibitors and ARBs work the other way: they can raise potassium, so do not add potassium on your own (see below). For the test or question that goes with each medicine, see what to ask your doctor or pharmacist.

Metformin and vitamin B12

Metformin, the most widely used diabetes drug, appears to interfere with vitamin B12 absorption in the lower small intestine. The effect is well documented:

• In a randomized trial of 390 people with type 2 diabetes who were also using insulin, 4.3 years of metformin lowered B12 by 19 percent compared with placebo, and the share who developed outright deficiency was 7.2 percentage points higher (about 7 more people in every 100).
• In the long-term Diabetes Prevention Program study of adults with prediabetes, the odds of B12 deficiency rose by about 13 percent for each year of metformin use. Larger daily doses and longer use carry more risk.
• In US national survey data from adults aged 50 and over, 5.8 percent of people with diabetes taking metformin had biochemical B12 deficiency, compared with 2.4 percent of those with diabetes not taking it.

What the official guidance says. The current US metformin label says metformin may lower B12 and advises measuring blood counts every year and vitamin B12 every 2 to 3 years. The American Diabetes Association's 2026 Standards of Care recommend considering periodic B12 checks in long-term users, especially with anemia or nerve symptoms. The accompanying text advises checking every year after more than 4 years of use, or when there are other risk factors such as a vegan diet or past stomach or bowel surgery. The two schedules differ, so ask which applies to you. Either way, do not stop or cut back metformin because of a B12 concern; the answer is testing and, if needed, B12.

Why it matters. Low B12 can cause or worsen numbness and tingling, the same symptoms as diabetic nerve damage, which is why guidelines say to check B12 before blaming diabetes alone. Even so, a meta-analysis (a study that pools the results of earlier studies) of 31 studies found no significant link between metformin and anemia or nerve damage overall, though its authors still recommended yearly B12 checks. The long Diabetes Prevention Program study, however, found more anemia in metformin users and more nerve damage among metformin users with low B12.

Does a supplement fix it? The label says low B12 on metformin appears to reverse quickly with B12 supplements. But a standard multivitamin may not be enough: in the US survey, B12-containing supplements were not linked to less deficiency in people with diabetes, and the authors noted that the 6 mcg in a typical multivitamin may be too little. A cross-sectional study of 1,111 Korean metformin users did find less deficiency among multivitamin users, so the evidence is mixed. For confirmed deficiency in general, a Cochrane review found low-quality evidence from two small trials that 1,000 mcg a day by mouth raised blood B12 about as well as injections. The best approach is a blood test first, then a dose matched to the result. See also our guides to B12 deficiency symptoms and the best B12 supplements.

Omeprazole and other PPIs: magnesium, B12 and iron

Proton pump inhibitors (PPIs) such as omeprazole (Prilosec), esomeprazole (Nexium) and pantoprazole (Protonix) cut stomach acid sharply. H2 blockers such as famotidine (Pepcid) are a milder type of acid reducer. Over long periods, both can affect a few nutrients.

Magnesium (rare, but can be serious). In 2011 the FDA warned that prescription PPIs may cause low magnesium when taken for a long time, in most cases more than a year. Low magnesium can cause muscle spasms, irregular heartbeat and seizures, though not everyone has symptoms. In about a quarter of the cases the FDA reviewed, magnesium supplements alone did not fix the problem and the PPI had to be stopped. The FDA suggested doctors consider checking magnesium before and during long-term treatment, especially in people who also take diuretics or digoxin (a heart medicine). It said the risk with over-the-counter PPIs used as directed (14-day courses) is very low. Magnesium is not part of the usual blood electrolyte panel, so it has to be ordered separately.

Vitamin B12 and iron (moderate). Stomach acid helps release B12 from food. In a large Kaiser Permanente study, 2 or more years of PPIs was linked to 65 percent higher odds of B12 deficiency, and 2 or more years of H2 blockers such as famotidine to 25 percent higher odds. A similar study linked 2 or more years of PPIs to about 2.5 times the odds of iron deficiency, with risk falling after people stopped. These are observational findings. The PPI label says B12 malabsorption may occur with daily use longer than about 3 years. The B12 in supplements and fortified foods is not bound to food protein, so it does not need stomach acid to be released.

Calcium and fractures (weaker). The labels warn of a possible higher risk of hip, wrist and spine fractures with long-term or high-dose use, based on observational studies. But a randomized trial of 17,598 people with heart or artery disease taking pantoprazole or placebo for about 3 years found no significant difference in safety outcomes, fractures included, other than gut infections.

Should you supplement? First, the FDA advises not stopping a prescription PPI without talking to your prescriber. The American Gastroenterological Association advises that long-term PPI users should not routinely raise their calcium, B12 or magnesium above the recommended amounts, and should not be routinely screened. Ask about testing if you also take a diuretic or digoxin. The FDA also advises seeking care right away for a racing or irregular heartbeat, palpitations, muscle spasms, tremor or seizures while taking a PPI. And because magnesium pills sometimes did not work until the PPI was stopped, self-treating can hide the cause. See our guide to supplements for GERD and acid reflux.

Do statins deplete CoQ10?

Statins block the body's cholesterol-making pathway, which also makes coenzyme Q10. Meta-analyses of randomized trials agree that statins lower CoQ10 in the blood. Whether levels fall inside muscle is less clear: a biopsy study found no drop with a standard statin dose, while another found a drop only with high-dose simvastatin.

Does taking CoQ10 help statin muscle aches? The evidence is split. Of five meta-analyses, three found no significant benefit and two found lower muscle pain scores. The negative ones pooled 6 trials (302 people), 7 studies (321 people) and 8 studies; the positive ones pooled 12 trials (575 people) and, in a 2025 analysis funded by a German vitamin research society, 7 trials (389 people). The trials were small and short. In one carefully designed trial, people who had muscle pain on a statin but not on placebo took 600 mg a day of ubiquinol or placebo for 8 weeks; pain rose with the statin whether or not they took CoQ10.

Most statin aches are not caused by the statin. A 2022 analysis of 19 double-blind, placebo-controlled trials found muscle pain or weakness in 27.1 percent of people on a statin and 26.6 percent on placebo, and concluded that more than 90 percent of muscle complaints reported by trial participants taking statins were not due to the drug. Statins did cause a small excess of mostly mild muscle pain, mainly in the first year. In a small trial of 60 people (SAMSON), about 90 percent of the symptom burden on statin tablets also appeared on placebo tablets. Researchers call this the nocebo effect: expecting a side effect can bring on real symptoms. In a UK trial of 200 people who had stopped or considered stopping statins because of muscle symptoms, symptom scores were the same on statin and placebo, and two-thirds of those who finished the trial chose to restart their statin.

What expert bodies say. The European Atherosclerosis Society does not recommend CoQ10 to treat or prevent statin muscle symptoms. The US National Lipid Association says well-designed trials are needed before recommending it, and the NIH's complementary health center says the evidence does not support it. We found no mention of CoQ10 depletion in the US atorvastatin (Lipitor) label. CoQ10 is generally well tolerated and some people try it, but it may interact with warfarin and with insulin. If you have muscle aches, talk with your prescriber, who can check for other causes or adjust the statin type or dose; do not stop the statin on your own. See our CoQ10 supplement ranking and supplement and drug interactions.

Diuretics: potassium, magnesium and calcium

Diuretics, often called water pills, lower blood pressure and fluid buildup by making the kidneys pass more salt and water. Loop diuretics (such as furosemide) and thiazides (such as hydrochlorothiazide and chlorthalidone) make the kidneys flush out more potassium and magnesium. Their labels warn about low potassium and low magnesium, and the furosemide label advises checking electrolytes periodically. Prescribers often handle this with potassium-rich foods, a potassium supplement they prescribe, or a potassium-sparing diuretic. Potassium is part of the basic blood panel; magnesium needs a separate test.

Do not add potassium on your own. Many people take a diuretic together with an ACE inhibitor, an ARB or spironolactone, and those medicines push potassium the other way. Only take a potassium supplement or a potassium salt substitute if your prescriber has checked your level and agrees, and if you take one of those medicines, ask whether you should limit high-potassium foods (see blood pressure medicines that raise potassium).

The calcium twist. Thiazides do the opposite with calcium: they reduce how much the kidneys excrete, and the label notes they can slightly raise blood calcium. According to the NIH Office of Dietary Supplements, combining thiazides with vitamin D supplements might lead to high calcium, especially in older adults and people with kidney problems or overactive parathyroid glands. Check with your doctor before taking high doses of calcium or vitamin D with a thiazide.

Loop diuretics have also been linked to lower thiamine (vitamin B1) in hospitalized heart failure patients, but that is a hospital setting, not a reason for everyday self-supplementing. Small studies suggest thiazides, ACE inhibitors and ARBs may lower blood zinc or raise zinc loss in urine, but they did not measure deficiency symptoms or account for diet.

Blood pressure medicines that raise potassium

This is the most important "do not supplement" warning in this guide. Spironolactone and other potassium-sparing diuretics, ACE inhibitors (such as lisinopril) and ARBs, short for angiotensin receptor blockers (such as losartan), reduce how much potassium the kidneys remove. ACE inhibitors and ARBs are two of the most common families of blood pressure medicines, also used for heart failure and to protect the kidneys in diabetes. The spironolactone and lisinopril labels warn that potassium supplements and potassium-containing salt substitutes raise the risk of dangerously high potassium, which can disturb the heart's rhythm. The spironolactone label advises patients to avoid potassium supplements and foods high in potassium, including salt substitutes, and the lisinopril label tells patients not to use potassium salt substitutes without asking their doctor.

Low-sodium salt substitutes made with potassium chloride lowered stroke rates in a large trial of older adults in rural China who had a past stroke or high blood pressure (see our salt substitute article), but if you take one of these medicines or have kidney disease, check with your prescriber first.

Seizure medicines: vitamin D, folate and B6

Older seizure medicines that speed up liver enzymes, especially phenytoin, carbamazepine and phenobarbital, can lower vitamin D. The phenytoin label warns that long-term use has been linked to lower bone density and fractures, and advises considering bone-related tests. A meta-analysis found vitamin D about 4 ng/mL lower in people taking carbamazepine. In a trial of adults on long-term seizure medicines, bone density rose at all measured sites with 4,000 IU of vitamin D a day but not with 400 IU, though it stayed below normal after a year.

Where replacing backfires. Phenytoin lowers folate, but folic acid can in turn lower phenytoin levels, so the dose may need adjusting. Phenytoin, carbamazepine and valproate can also lower vitamin B6, yet some research shows 200 mg a day of B6 can reduce phenytoin and phenobarbital levels. If you take a seizure medicine, ask your neurologist before taking folate, high-dose B6 or other supplements.

Methotrexate and folic acid

Low-dose, once-weekly methotrexate for rheumatoid arthritis, psoriasis and some other conditions works partly by blocking folate. The label tells prescribers to give folic acid or folinic acid to these patients to reduce side effects. A Cochrane review of 6 trials (624 people) in rheumatoid arthritis found folic or folinic acid cut stomach and gut side effects by about a quarter and abnormal liver tests by about three-quarters, and fewer people stopped methotrexate. But the dose and timing are set by the prescriber. For methotrexate used to treat cancer, the label says not to take folic acid products unless the oncologist directs it, because they may reduce the drug's effect.

Levodopa, isoniazid, orlistat and steroids

• Carbidopa/levodopa (Parkinson's disease) and vitamin B6. In 2026 the label gained a warning that it may lower vitamin B6, especially at higher doses, and that seizures from B6 deficiency have been reported that resolved only after B6 was given. It now advises checking B6 before starting and periodically, and supplementing if low. The old advice to avoid B6 applied to levodopa without carbidopa; the label says the combination can be taken with B6. High-dose B6 has its own risk of nerve damage, so test rather than megadose.
• Isoniazid (tuberculosis) and vitamin B6. The label recommends B6 for people who are malnourished or prone to nerve problems, and the CDC advises 25 to 50 mg a day for people at risk, such as those who are pregnant or have diabetes, HIV, kidney failure or alcohol use problems. This is prescribed with the treatment.
• Orlistat (weight loss) and fat-soluble vitamins. The label advises a multivitamin with vitamins A, D, E and K once a day, at least 2 hours before or after orlistat or at bedtime. In trials, more people on orlistat had low vitamin D (12 versus 7 percent).
• Cholestyramine (cholesterol) and vitamins. The label notes it may block absorption of vitamins A, D, E and K, and folate with long-term use, and suggests considering supplements. Because it can bind other medicines, the label advises taking other drugs at least 1 hour before or 4 to 6 hours after it.
• Long-term steroids (such as prednisone) and bone. Steroids reduce calcium absorption and weaken bone. The American College of Rheumatology's patient guidance advises at least 1,200 mg of calcium and 800 to 1,000 IU of vitamin D a day for people on long-term steroids. The college's 2022 guideline also strongly recommends a fracture risk assessment soon after starting steroids for more than 3 months, and bone-protecting medicine for people at medium or higher fracture risk.

Does birth control deplete nutrients?

Online lists claim the pill drains many vitamins and minerals. The evidence is narrower:

• Vitamin B6: US survey data found most users of hormonal birth control pills had low blood B6, and a review concluded current low-dose pills may lower B6 status. But feeding studies did not find higher B6 needs in pill users, and a 2018 review (the supplement-company-linked review described below) said widespread supplementing is not currently recommended.
• Folate: a review concluded the evidence does not support the idea that today's pills harm folate status. Separately, the US Preventive Services Task Force recommends 400 to 800 mcg of folic acid a day for everyone who could become pregnant, pill or not (see folate vs folic acid).
• Vitamin B12: blood B12 is often lower in pill users, but the markers that show B12 shortage in tissues were not affected, which suggests the vitamin is redistributed rather than depleted.

Are nutrient depletion charts reliable?

Some widely shared charts say they were compiled from a drug-induced nutrient depletion handbook first published in 1999, and similar lists are repeated by supplement retailers. They often pair CoQ10 with metformin, B vitamins with diuretics, and a long list of minerals with birth control. Even a 2018 review written partly by employees of a supplement company noted that drug-nutrient resources "simply repeat the same lists of outdated or obscure examples" and that research on drug-nutrient interactions is far thinner than on drug-drug interactions. In a small 16-week trial in adults aged 45 to 75 taking diuretics, metformin or PPIs (54 finished), average blood levels of the vitamins and minerals measured were within normal ranges at the start.

A multivitamin is a reasonable safety net for some people (see do you need a multivitamin?), but it is not a fix for a true deficiency, and it is no substitute for the specific testing the labels and guidelines describe. Newer drugs such as GLP-1 weight-loss medicines are not known to block nutrient absorption the way the drugs above do. A 2026 review linked possible shortfalls to eating less and less varied food, stomach side effects and slower stomach emptying, and found the evidence too limited to show a direct effect (see supplements to take with Ozempic).

What to ask your doctor or pharmacist

• Metformin: "When should my vitamin B12 be checked?" (a blood B12 test, plus a methylmalonic acid, or MMA, test if the result is borderline; MMA rises when the body is short of B12).
• Prescription PPI for over a year, especially with a diuretic or digoxin: "Should my magnesium be checked?" Seek care right away for palpitations, a racing or irregular heartbeat, muscle spasms, tremor or seizures.
• Loop or thiazide diuretic: potassium and magnesium checks; ask before high-dose calcium or vitamin D with a thiazide.
• Spironolactone, ACE inhibitor or ARB: regular potassium checks; no potassium supplements or salt substitutes unless approved.
• Phenytoin or other older seizure drugs: bone and vitamin D checks; ask before folate or B6.
• Carbidopa/levodopa: a vitamin B6 level before starting and periodically.
• Low-dose methotrexate: take folic acid exactly as prescribed.
• Orlistat: a multivitamin at least 2 hours apart or at bedtime.
• Long-term steroids: calcium, vitamin D and a fracture risk assessment.

Bring a list of every supplement you take, since some also interact with medicines. Taking extra beyond what you need is not risk-free; see our guide to upper limits and megadosing.

Frequently asked questions

Which medications deplete nutrients?

The best-documented examples are metformin (vitamin B12), long-term proton pump inhibitors (magnesium, and B12 and iron after years), loop and thiazide diuretics (potassium and magnesium), phenytoin (vitamin D and bone), carbidopa/levodopa and isoniazid (vitamin B6), orlistat and cholestyramine (vitamins A, D, E and K), long-term steroids (calcium and bone) and low-dose methotrexate (folate). Many other pairings on online charts have weak evidence.

Does metformin cause B12 deficiency?

It can. In a 4-year trial metformin lowered B12 by 19 percent compared with placebo, and risk rises with dose and years of use. The US label advises checking B12 every 2 to 3 years, and the American Diabetes Association advises periodic checks, yearly after more than 4 years of use or with other risk factors.

How much B12 should I take with metformin?

Get your level tested first. If you are low, your clinician will choose a dose; for B12 deficiency in general, 1,000 mcg a day by mouth raised blood levels about as well as injections in two small trials in a Cochrane review (low-quality evidence). A standard multivitamin, with about 6 mcg, may not be enough to correct a deficiency.

Do statins deplete CoQ10?

Statins lower CoQ10 in the blood, because they block the pathway that makes both cholesterol and CoQ10. Whether muscle levels fall is unclear, and we found no mention of CoQ10 depletion in the US atorvastatin (Lipitor) label.

Should I take CoQ10 with my statin?

The evidence is unsettled: meta-analyses disagree on whether CoQ10 eases statin muscle aches, and European lipid experts do not recommend it. Most aches in people on statins are not caused by the drug. CoQ10 is generally well tolerated but may interact with warfarin and insulin, so talk with your prescriber, and do not stop a statin on your own.

Does omeprazole deplete magnesium or B12?

Long-term use of prescription proton pump inhibitors such as omeprazole can rarely cause low magnesium, usually after more than a year, according to the FDA. It can be serious, and in some cases magnesium supplements did not help until the PPI was stopped. Do not stop a prescription PPI on your own; seek care right away for palpitations, muscle spasms, tremor or seizures. The FDA considers the risk very low with over-the-counter 14-day courses used as directed. Two or more years of PPI use has also been linked to higher odds of B12 deficiency in a large observational study, and the label says B12 absorption may suffer with daily use longer than about 3 years. Ask your prescriber about testing.

What medications deplete potassium?

Loop diuretics such as furosemide and thiazides such as hydrochlorothiazide can lower potassium. Spironolactone, ACE inhibitors and ARBs do the opposite and can raise potassium, so people taking them should not use potassium supplements or potassium salt substitutes unless their prescriber agrees.

What medications cause B12 deficiency?

The best-documented is metformin, which lowered B12 by 19 percent compared with placebo in a 4-year trial. Long-term acid reducers are also linked to B12 deficiency: 2 or more years of a PPI such as omeprazole, or of an H2 blocker such as famotidine, was tied to higher odds in a large observational study. Birth control pills are often linked to lower blood B12, but other markers suggest this is a shift in how B12 is carried, not a true shortage. A blood test is the way to know; do not stop or change a prescribed medicine because of a B12 concern.

What vitamins does birth control deplete?

The best evidence is for lower vitamin B6. Reviews do not support claims that today's pills cause folate deficiency, and lower blood B12 in pill users appears to reflect a shift in where B12 is carried rather than a true shortage. Anyone who could become pregnant is advised to take 400 to 800 mcg of folic acid a day regardless.

Should people who take medications use a multivitamin?

It can be a reasonable safety net, and the orlistat label specifically recommends one taken at least 2 hours apart from the drug. But a multivitamin may not correct a true deficiency such as low B12 on metformin, so specific testing is better than guessing.

Can supplements interfere with medicines?

Yes. Folic acid and high-dose vitamin B6 can lower phenytoin levels, potassium is risky with spironolactone, ACE inhibitors and ARBs, high-dose calcium and vitamin D can raise calcium too far with thiazides, and folic acid should only be used with methotrexate as prescribed. Always tell your doctor or pharmacist what you take.

The bottom line

A handful of medicine and nutrient pairings are well documented and written into US labels or guidelines; the biggest are metformin and B12, long-term PPIs and magnesium, and diuretics with potassium and magnesium (the table above lists the rest). Statins do lower CoQ10 in the blood, but whether CoQ10 pills help muscle aches is unsettled, and most aches turn out not to come from the statin.

The safest approach is to test rather than guess, take what a test or your prescriber says you need, and never stop a medicine on your own. Watch for the cases where supplements cause harm: potassium with spironolactone, ACE inhibitors or ARBs; high-dose calcium and vitamin D with thiazides; and folic acid or high-dose B6 with phenytoin.