What medications can cause vitamin deficiencies and which vitamins are affected?

Medications That Cause Vitamin Deficiencies

Multiple commonly prescribed medications cause clinically significant vitamin and mineral deficiencies that require monitoring and often supplementation, with metformin, proton pump inhibitors, anticonvulsants, and bile acid sequestrants being the most important offenders.

Antidiabetic Medications

Metformin

• Vitamin B12 deficiency is the primary concern with chronic metformin use, with patients more likely to develop deficiency (≤203 pg/mL), anemia, and elevated homocysteine after 5 years of treatment 1
• Periodic evaluation of vitamin B12 status is justified in all patients taking metformin, particularly in high-risk populations including the elderly, vegetarians/vegans, and those on multiple medications 1
• The deficiency can cause irreparable neuropathic damage if undiagnosed, making early detection critical 1

Gastric Acid-Suppressing Drugs

Proton Pump Inhibitors (PPIs)

• Vitamin B12 deficiency occurs with chronic PPI use, particularly at higher doses (>1.5 pills/day) and duration ≥2 years (OR: 1.95) 1
• Iron deficiency is strongly associated with ≥2 years of PPI use, especially at higher doses (≥1.5 pills/day; adjusted OR: 2.49) 1
• Calcium and magnesium deficiency can occur, with PPIs associated with increased hip fracture risk (RR: 1.20) and hypomagnesemia 1
• Vitamin D deficiency may develop due to impaired calcium absorption 1

Cardiovascular Medications

Thiazide Diuretics (Chlorthalidone, Hydrochlorothiazide)

• Potassium deficiency (hypokalemia <3.5 mmol/L) occurs in 7.2-8.5% of patients after 1-4 years of treatment 1
• Magnesium deficiency (hypomagnesemia) develops in a dose-dependent manner, with chlorthalidone having higher potency than hydrochlorothiazide 1
• Supplementation is required in approximately 8% of patients on chlorthalidone after 5 years 1

Bile Acid Sequestrants (Colesevelam, Cholestyramine, Colestipol)

• Fat-soluble vitamin deficiencies (A, D, E, K) can occur due to binding and reduced absorption 1
• Folate deficiency may develop with cholestyramine use 2
• Oral vitamins should be given ≥4 hours before these medications to prevent binding 1
• Monitor INR frequently in patients on warfarin due to vitamin K interaction 1

Anticonvulsant Medications

Phenytoin

• Vitamin D deficiency develops through increased CYP450-mediated metabolism of vitamin D3, leading to osteomalacia, bone fractures, osteoporosis, hypocalcemia, and hypophosphatemia in chronically treated patients 3
• Vitamin B6 (pyridoxine) deficiency occurs in 48% of patients taking enzyme-inducing anticonvulsants like phenytoin, often severe 4

Carbamazepine and Valproic Acid

• Multiple B-vitamin deficiencies including B6, B12, and folate 5
• Calcium and vitamin D deficiency 5
• Vitamin E deficiency with both carbamazepine and valproic acid 5
• Selenium, carnitine, and zinc deficiency specifically with valproic acid 5

Rheumatologic Medications

Methotrexate

• Folic acid deficiency occurs through potent inhibition of dihydrofolate reductase, preventing conversion to the active form of folate 2
• Prophylactic folic acid supplementation (1-5 mg daily) is recommended for all patients on methotrexate 2
• Monitor for macrocytic anemia, fatigue, and neurological symptoms 2

Sulfasalazine

• Folic acid deficiency develops through impaired folate absorption and metabolism, particularly important in inflammatory bowel disease and rheumatoid arthritis patients 2
• Prophylactic folic acid supplementation is recommended 2

Antimicrobial Medications

Trimethoprim/Sulfamethoxazole (TMP-SMX)

• Folic acid deficiency occurs through direct inhibition of dihydrofolate reductase 2

Isoniazid (INH) and Cycloserine

• Vitamin B6 (pyridoxine) deficiency develops through interference with B6 metabolism 6
• Secondary niacin deficiency may occur 6

Psychiatric Medications

Tricyclic Antidepressants (TCAs)

• Multiple B-vitamin deficiencies 5
• Calcium and vitamin D deficiency 5
• Coenzyme Q10 deficiency 5

Antipsychotics

• Multiple B-vitamin deficiencies 5
• Calcium and vitamin D deficiency 5
• Selenium deficiency specifically with clozapine 5

Lithium

• Various B-vitamin deficiencies 5

Other Medications

Oral Contraceptives

• Folic acid deficiency 6
• Ascorbic acid (vitamin C) deficiency 6
• Riboflavin (vitamin B2) deficiency in cases of deficient nutrition 6

Colchicine

• Vitamin B12 deficiency 1

H2 Receptor Antagonists

• Vitamin B12 deficiency 1

Pregabalin, Phenobarbital, and Primidone

• Vitamin B12 deficiency 1

Clinical Management Considerations

Key monitoring recommendations:

• Identify at-risk patients taking these medications, particularly those with pre-existing marginal vitamin status, elderly patients, those on multiple medications, or with restricted diets 1
• Most symptomatic deficiencies develop only with prolonged use (typically ≥2 years) in patients already at risk 1, 7
• Widespread supplementation is not recommended; instead, identify at-risk individuals for targeted evaluation and treatment 5
• For established deficiencies, treatment with oral supplementation (e.g., folic acid 5 mg daily for ≥4 months) is typically effective 2

Common pitfall: Vitamin deficiencies from medications are often overlooked because symptomatic avitaminosis is unusual with therapeutic doses administered for brief periods to patients receiving adequate nutrition 7. However, chronic use in vulnerable populations can cause severe, clinically significant deficiencies requiring proactive monitoring 1.