--- topic: "Medication Nutrient Depletion" title: "Which Medications Deplete Nutrients?" order: 1 description: "Which common medicines lower vitamin B12, magnesium, iron or potassium, which links are weak, and what to ask your prescriber instead of guessing." question: "Which common medications deplete vitamins and minerals?" answer: "Metformin, acid-reducing drugs and diuretics likely deplete B12, magnesium, iron or potassium over time; ask about blood tests rather than guessing or stopping." actions: - "If you take metformin, ask your clinician about a vitamin B12 blood test, especially after several years or if you have numbness, tingling or anemia [1][2]." - "If you have taken a PPI or H2 blocker for two years or more, ask whether you still need it, and about B12, magnesium and iron levels [3][4][5]." - "Test before you supplement: reviews do not recommend routine supplementing, but people at risk should reach recommended intakes from food or, where needed, supplements [10]." cautions: - "Do not stop a prescribed medicine to avoid a nutrient loss: stopping a PPI, for example, should rest on whether you still need it, not on side-effect worries alone [12]." - "Mineral levels can be disturbed in both directions, so take potassium or magnesium only on your prescriber's or pharmacist's advice [6]." - "Planning a pregnancy while on the pill? Ask about folate and vitamin B6, because low-dose pill users may have lower B6 [9]." confidence: 3 confidenceNote: "Randomized trials support the metformin and B12 link, but the acid-reducer and diuretic links are mostly observational and several others are weak or mixed." evidenceSummary: rctCount: 3 observationalCount: 3 metaAnalysisCount: 3 totalParticipants: "230,000+ in the largest case-control studies" replicated: true newestStudyYear: 2022 references: - id: "1" pmid: "26900641" title: "Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study" authors: "Aroda VR, Edelstein SL, Goldberg RB, et al." year: 2016 journal: "J Clin Endocrinol Metab" - id: "2" pmid: "20488910" title: "Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial" authors: "de Jager J, Kooy A, Lehert P, et al." year: 2010 journal: "BMJ" - id: "3" pmid: "24327038" title: "Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency" authors: "Lam JR, Schneider JL, Zhao W, et al." year: 2013 journal: "JAMA" - id: "4" pmid: "26108134" title: "Proton pump inhibitors linked to hypomagnesemia: a systematic review and meta-analysis of observational studies" authors: "Cheungpasitporn W, Thongprayoon C, Kittanamongkolchai W, et al." year: 2015 journal: "Ren Fail" - id: "5" pmid: "27890768" title: "Proton Pump Inhibitor and Histamine-2 Receptor Antagonist Use and Iron Deficiency" authors: "Lam JR, Schneider JL, Quesenberry CP, et al." year: 2017 journal: "Gastroenterology" - id: "6" pmid: "23332973" title: "Electrolyte disorders in community subjects: prevalence and risk factors" authors: "Liamis G, Rodenburg EM, Hofman A, et al." year: 2013 journal: "Am J Med" - id: "7" pmid: "30371340" title: "Effects of Coenzyme Q10 on Statin-Induced Myopathy: An Updated Meta-Analysis of Randomized Controlled Trials" authors: "Qu H, Guo M, Chai H, et al." year: 2018 journal: "J Am Heart Assoc" - id: "8" pmid: "25440725" title: "Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials" authors: "Banach M, Serban C, Sahebkar A, et al." year: 2015 journal: "Mayo Clin Proc" - id: "9" pmid: "21967158" title: "Oral contraceptive use: impact on folate, vitamin B6, and vitamin B12 status" authors: "Wilson SM, Bivins BN, Russell KA, et al." year: 2011 journal: "Nutr Rev" - id: "10" pmid: "29558445" title: "Evidence of Drug-Nutrient Interactions with Chronic Use of Commonly Prescribed Medications: An Update" authors: "Mohn ES, Kern HJ, Saltzman E, et al." year: 2018 journal: "Pharmaceutics" - id: "11" pmid: "7978695" title: "Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial" authors: "Morgan SL, Baggott JE, Vaughn WH, et al." year: 1994 journal: "Ann Intern Med" - id: "12" pmid: "35183361" title: "AGA Clinical Practice Update on De-Prescribing of Proton Pump Inhibitors: Expert Review" authors: "Targownik LE, Fisher DA, Saini SD" year: 2022 journal: "Gastroenterology" --- Metformin can lower vitamin B12 [1][2]. Long-term acid-reducing drugs (PPIs and H2 blockers) are linked to low B12, magnesium and iron [3][4][5], and thiazide diuretics to low sodium, potassium and magnesium [6]. Links for statins and CoQ10, or the pill and B vitamins, are weaker or mixed [7][8][9]. Ask about blood tests, and never stop a prescribed medicine on your own. ## How it works ### Why drugs change nutrient status Acid-reducing drugs cut stomach acid, which can impair absorption of B12 and iron [3][5]; other drugs are linked to low levels by routes that are less clear. The effect can build slowly, over months or years, and for most of these interactions there are too few high-quality intervention trials to say what to do about them [10]. ### The strongest links - **Metformin and vitamin B12.** In the Diabetes Prevention Program Outcomes Study, low B12 was more common on metformin than placebo at 5 years (4.3 versus 2.3 percent), and each year of use raised the odds of deficiency by 13 percent [1]. In a 4.3-year Dutch trial, B12 fell 19 percent more on metformin than placebo [2]. See [vitamin B12](/vitamin-b12/neurological-energy-and-who-needs-it). - **Acid-reducing drugs.** Two or more years of a PPI went with 65 percent higher odds of B12 deficiency (25 percent for H2 blockers) [3], with low magnesium (risk ratio 1.43) [4] and with iron deficiency (odds ratio 2.49, falling after the drug was stopped) [5]. See [acid reflux](/acid-reflux/natural-management) and [magnesium](/magnesium/why-magnesium-matters). - **Diuretics.** In adults 55 and older, thiazides were linked to low sodium, potassium and magnesium, and loop diuretics to low potassium [6]. ### Weaker or mixed links - **Statins and CoQ10.** CoQ10 supplements eased statin muscle symptoms in a 12-trial meta-analysis [7] but not in an earlier 6-trial one [8]; both pooled small trials. For what large trials say about statin muscle symptoms, see [what lowers cholesterol](/high-cholesterol/what-lowers-cholesterol-naturally). - **The pill and B vitamins.** Current data do not show lower folate; low-dose pills may lower vitamin B6; B12 markers were not affected [9]. ### Where a supplement is standard care Folic acid alongside methotrexate is an example where supplementing works: in a 79-person trial in rheumatoid arthritis it lowered toxicity without reducing the drug's effect [11]. This is prescriber-directed, not a do-it-yourself fix. ### What to do If you have taken one of these medicines for years, or have numbness, tingling or anemia, ask for the relevant blood tests. A PPI should be reviewed regularly to confirm you still need it, and the decision to stop should rest on that, not on side-effect worries alone [12]. See [common medications and their hidden costs](/pharmaceutical-side-effects/common-medications) and [safely reducing or stopping a medication](/pharmaceutical-side-effects/safely-reducing-or-stopping-medications). ## The evidence in detail ### Metformin and B12 The Diabetes Prevention Program assigned 2,155 people to placebo (n=1,082) or metformin 850 mg twice daily (n=1,073) for 3.2 years, then offered the metformin group 9 more years of open-label metformin. Low B12 (at or below 203 pg/mL) was more common on metformin at 5 years (4.3 versus 2.3 percent; P=.02) but not at 13 years (7.4 versus 5.4 percent; P=.12). Low or borderline-low B12 (at or below 298 pg/mL) was more common at both points (19.1 versus 9.5 percent, and 20.3 versus 15.6 percent). Anemia was more common on metformin but did not track B12 status, and neuropathy was more common in metformin users with low B12 [1]. In the Dutch trial, 390 insulin-treated people with type 2 diabetes took metformin 850 mg or placebo three times daily for 4.3 years. B12 was 19 percent lower on metformin (95% CI 14 to 24), the absolute risk of deficiency (below 150 pmol/L) was 7.2 percentage points higher (number needed to harm 13.8 over 4.3 years), and homocysteine was higher in deficient patients [2]. ### Acid-reducing drugs A Kaiser Permanente case-control study compared 25,956 patients with new B12 deficiency with 184,199 controls. A supply of PPIs for two or more years carried an odds ratio of 1.65 (95% CI 1.58 to 1.73) and H2 blockers 1.25 (1.17 to 1.34); more than 1.5 pills a day was stronger (1.95) than under 0.75 (1.63) [3]. A meta-analysis of nine observational studies (109,798 patients) found a pooled risk ratio of 1.43 (1.08 to 1.88) for low magnesium in PPI users [4]. In a case-control study of 77,046 people with new iron deficiency and 389,314 controls, two or more years of PPIs had an odds ratio of 2.49 (2.35 to 2.64) and H2 blockers 1.58 (1.46 to 1.71). The association was stronger at higher doses (4.27 for more than 1.5 pills a day for 10 years or more) and weaker after stopping [5]. ### Diuretics In the Rotterdam Study of 5,179 people aged 55 and older, 15.0 percent had at least one electrolyte disorder. Thiazides were independently associated with low sodium, potassium and magnesium; loop diuretics with high sodium and low potassium; potassium-sparing diuretics with low sodium. Low sodium and low magnesium were linked to higher mortality [6]. ### Statins, CoQ10, the pill and methotrexate The 2018 meta-analysis of 12 trials (575 patients) found CoQ10 reduced muscle pain (weighted mean difference -1.60), weakness, cramps and tiredness, with no change in creatine kinase [7]. The 2015 meta-analysis of 6 trials (302 patients) found no significant effect on muscle pain (standardized mean difference -0.53, 95% CI -1.33 to 0.28) or creatine kinase, and called for larger trials [8]. For the pill, a review concluded that current data do not support lower folate status, that low-dose pills may lower vitamin B6, and that functional B12 indicators are not significantly affected, with definitive answers awaiting more work [9]. In the methotrexate trial, 79 people with rheumatoid arthritis took placebo or 5 mg or 27.5 mg of folic acid weekly. Folic acid left efficacy unchanged and lowered toxicity scores (P at or below .001) [11]. ### Where the evidence conflicts Most acid-reducer and diuretic data are observational, so differences between people who take these drugs and people who do not cannot be ruled out [3][4][5][6]. The two CoQ10 meta-analyses disagree [7][8]. A low lab value is not always illness: in the metformin study, anemia did not track B12 status [1]. A review of commonly prescribed drugs concluded that most interactions need better trials, that widespread supplementation is not recommended, and that at-risk patients should reach recommended intakes [10]. The American Gastroenterological Association advises regular review of every PPI prescription, a trial of de-prescribing when there is no definite indication, a warning about rebound acid symptoms, and basing the decision to stop on lack of indication rather than adverse-event worries [12]. ### Bottom line Confidence is moderate (3 of 5). Metformin lowers B12 in randomized trials [1][2], and acid reducers and diuretics are linked to low B12, iron, magnesium and potassium in large observational studies [3][4][5][6]. Statin-CoQ10 and pill-B vitamin links are weak or mixed [7][8][9]. The practical step is a blood test and a medicine review, not a self-started supplement or a stopped prescription.