Medication-Induced Nutrient Depletion: The Complete Reference
Every medication has a mechanism. And every mechanism has a cost.
Medication-Induced Nutrient Depletion: The Complete Reference
The Silent Side Effect No One Mentions
Every medication has a mechanism. And every mechanism has a cost. When a drug blocks an enzyme, alters pH, changes membrane transport, or disrupts a metabolic pathway to achieve its therapeutic effect, it inevitably affects nutrient status somewhere downstream. This is not a rare complication — it is a pharmacological certainty.
The tragedy is not that these depletions occur. The tragedy is that they are almost never addressed. A patient takes a statin for twenty years and nobody mentions CoQ10. A woman takes oral contraceptives for a decade and nobody checks her B6, folate, or magnesium. An elderly patient on metformin and a PPI develops fatigue, brain fog, and neuropathy — and is prescribed more medications instead of having their B12 and magnesium tested.
In functional medicine, the medication list is the first place we look for root causes of nutrient deficiency. This is not anti-medication. It is pro-patient. Every drug has a role. Every drug has a nutrient cost. Both can be managed simultaneously.
Proton Pump Inhibitors (PPIs)
Drugs: Omeprazole (Prilosec), pantoprazole (Protonix), esomeprazole (Nexium), lansoprazole (Prevacid)
PPIs suppress gastric acid production by 90-99%. Stomach acid is not just for digestion — it is the gatekeeper for mineral absorption and the first line of defense against ingested bacteria.
Nutrient depletions:
- Vitamin B12: Gastric acid is required to cleave B12 from food proteins. Without acid, B12 remains bound and passes through unabsorbed. Long-term PPI use (>2 years) increases B12 deficiency risk by 65% (Lam 2013). Sublingual or intramuscular B12 bypasses this mechanism.
- Magnesium: PPIs impair active and passive intestinal magnesium absorption. The FDA issued a safety warning in 2011 about PPI-induced hypomagnesemia — potentially causing seizures, arrhythmias, and tetany. Cases are resistant to oral magnesium supplementation while the PPI continues.
- Calcium: Acid-dependent absorption. Calcium carbonate requires acid to ionize; calcium citrate does not (use citrate form for patients on PPIs). Long-term PPI use increases hip fracture risk by 25-50% (Yang 2006).
- Iron: Non-heme iron absorption requires acid reduction from ferric (Fe3+) to ferrous (Fe2+) form. Long-term PPI use significantly impairs iron status.
- Vitamin C: Gastric acid maintains vitamin C in its reduced, absorbable form. PPI use reduces vitamin C absorption and gastric juice vitamin C concentrations.
- Zinc: Acid-dependent absorption impaired.
Additional risk: PPI-induced hypochlorhydria increases SIBO risk (small intestinal bacterial overgrowth) by 2-3x. Gastric acid normally sterilizes ingested bacteria; without it, colonization of the small intestine is facilitated.
Clinical protocol: For patients who require PPIs, supplement B12 (sublingual 1000-5000mcg), magnesium (glycinate or threonate 400mg), calcium citrate (500mg with D3/K2), iron bisglycinate (if ferritin is low — every other day per Stoffel protocol), zinc picolinate (15-30mg), and vitamin C (500-1000mg). Reassess PPI necessity every 3-6 months — many patients can step down to H2 blockers or address root cause (H. pylori, food sensitivities, stress).
Metformin
The most prescribed diabetes medication worldwide.
Nutrient depletions:
- Vitamin B12: The de Jager 2010 randomized placebo-controlled trial (390 patients over 4.3 years) demonstrated that metformin decreased B12 levels by approximately 19%, with B12 deficiency occurring in 7.2% of treated patients vs 2.3% of controls by study end. The mechanism: metformin interferes with calcium-dependent B12-intrinsic factor absorption in the ileum.
- Folate: Reduced absorption through similar ileal mechanisms. Less dramatic than B12 but clinically relevant, especially with MTHFR variants.
Clinical impact: Metformin-induced B12 deficiency causes peripheral neuropathy — the exact symptom attributed to “diabetic neuropathy.” Patients are prescribed gabapentin for neuropathy caused by their diabetes medication’s nutrient depletion. The irony is clinical malpractice when the cause is knowable and treatable.
Clinical protocol: Every metformin patient requires annual B12 monitoring (MMA is more sensitive than serum B12). Supplement methylcobalamin or hydroxocobalamin 1000-5000mcg sublingual. Add methylfolate 400-800mcg. This should be standard of care for every metformin prescription.
Statins
Drugs: Atorvastatin (Lipitor), rosuvastatin (Crestor), simvastatin (Zocor), pravastatin (Pravachol)
Statins inhibit HMG-CoA reductase — the rate-limiting enzyme in cholesterol synthesis. The same pathway produces CoQ10.
Nutrient depletions:
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Coenzyme Q10: HMG-CoA reductase is required for both cholesterol AND CoQ10 synthesis. Statin use reduces CoQ10 levels by 40-50% (Ghirlanda 1993). Statin-associated myalgia (muscle pain), fatigue, exercise intolerance, and cognitive complaints are often CoQ10 depletion manifestations.
The Q-SYMBIO trial (Mortensen 2014) demonstrated that 300mg CoQ10 in heart failure patients (many on statins) reduced cardiovascular mortality by 43%. CoQ10 supplementation is not optional for statin users — it is a pharmacological necessity.
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Vitamin D: Statins may impair vitamin D synthesis through shared cholesterol pathway intermediates. Some studies show reduced 25-OH levels; others don’t. Worth monitoring.
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Selenium: Statins may reduce selenoprotein synthesis. Clinical significance is debated but selenium is inexpensive to supplement.
Clinical protocol: Every statin patient receives CoQ10 100-200mg (ubiquinol form for those over 40). Monitor vitamin D. Consider selenium 200mcg. Recheck CoQ10 levels if myalgia persists despite supplementation.
Oral Contraceptives
The most extensively studied medication-nutrient depletion pattern.
Nutrient depletions (Palmery 2013 systematic review):
- Vitamin B6: OCs increase tryptophan metabolism through the kynurenine pathway, depleting B6. This may contribute to OC-associated depression through reduced serotonin synthesis (B6 is required for tryptophan-to-serotonin conversion).
- Folate: OCs impair folate absorption and increase folate catabolism. Critical concern: women discontinuing OCs to become pregnant may be folate-depleted at conception — the period of highest need for neural tube prevention.
- Vitamin B12: Reduced serum levels through unclear mechanism. May affect binding proteins rather than true tissue depletion, but supplementation is prudent.
- Magnesium: Increased urinary excretion.
- Zinc: Decreased serum levels, increased copper levels (OCs raise ceruloplasmin). The zinc:copper ratio shifts unfavorably.
- Selenium: Reduced levels.
- Vitamin C: Increased utilization and decreased serum levels.
- CoQ10: Reduced levels (mechanism similar to statins — may involve shared synthesis pathway effects).
- Vitamin E: Reduced antioxidant capacity.
Clinical protocol: Every woman on oral contraceptives should take a high-quality prenatal-grade multivitamin containing methylfolate (not folic acid), P5P (active B6), methylcobalamin, magnesium, zinc, selenium, vitamin C, CoQ10, and vitamin E. This is especially critical in the months before and after discontinuing OCs for family planning.
Antibiotics
All classes.
Nutrient depletions:
- B vitamins (multiple): Gut bacteria synthesize vitamin K, B12, biotin, folate, riboflavin, and thiamine. Broad-spectrum antibiotics devastate these populations, reducing endogenous vitamin production for weeks to months.
- Vitamin K: Gut flora produce a significant portion of vitamin K2. Antibiotic courses can cause functional K2 depletion, potentially affecting clotting (K1) and calcium metabolism (K2).
- Gut microbiome itself: The most significant “nutrient” depleted is the microbiome. A single course of ciprofloxacin reduces microbial diversity by 25% (Dethlefsen 2011), with some species never recovering. This is not a temporary inconvenience — it is an ecological disruption with lasting metabolic, immune, and neurological consequences.
Clinical protocol: During antibiotics: Saccharomyces boulardii (yeast-based probiotic, not killed by antibacterial antibiotics) 500mg twice daily. B-complex. Vitamin K2 200mcg. After completion: high-dose multi-strain probiotic (50-100 billion CFU) for 1-3 months, fermented food reintroduction, prebiotic fiber (GOS, FOS, partially hydrolyzed guar gum) to feed recovering populations.
Corticosteroids
Drugs: Prednisone, prednisolone, dexamethasone, hydrocortisone, methylprednisolone
Long-term corticosteroid use causes predictable and severe nutrient depletion through multiple mechanisms — increased urinary excretion, impaired absorption, altered metabolism, and increased utilization.
Nutrient depletions:
- Calcium + Vitamin D: Steroids directly impair intestinal calcium absorption, increase renal calcium excretion, and inhibit osteoblast activity. Steroid-induced osteoporosis is the most common form of drug-induced bone loss.
- Vitamin C: Steroids increase oxidative stress while depleting the body’s primary water-soluble antioxidant.
- Zinc: Increased urinary excretion under cortisol influence.
- Magnesium: Increased urinary excretion.
- Chromium: Steroid-induced insulin resistance increases chromium requirements.
- Potassium: Mineralocorticoid effects promote potassium excretion, especially with fludrocortisone.
Clinical protocol: Calcium citrate 500mg with D3 2000-5000 IU and K2 200mcg (bone protection). Vitamin C 1-2g. Zinc 30mg with copper 2mg. Magnesium 400mg. Chromium 200-400mcg. Monitor potassium. DEXA bone density scan if steroids continue beyond 3 months.
Diuretics
Thiazides (hydrochlorothiazide): Deplete magnesium, potassium, zinc, sodium, CoQ10. Paradoxically spare calcium (may slightly increase calcium retention).
Loop diuretics (furosemide, bumetanide): Deplete magnesium, potassium, calcium, zinc, B1, B6, vitamin C. More aggressive mineral wasting than thiazides.
Potassium-sparing diuretics (spironolactone, amiloride): Can cause hyperkalemia — monitor carefully. Still deplete magnesium and zinc.
Clinical protocol: Electrolyte panel including RBC magnesium, zinc, and potassium with every diuretic prescription. Supplement magnesium 400mg, zinc 15-30mg (with copper 1-2mg), and replace potassium as needed. B-complex for loop diuretic users. Vitamin C 500mg.
SSRIs/SNRIs
Drugs: Fluoxetine (Prozac), sertraline (Zoloft), escitalopram (Lexapro), duloxetine (Cymbalta), venlafaxine (Effexor)
Nutrient depletions and interactions:
- Folate (methylation): SSRIs increase demand for methyl group donation. Patients with MTHFR variants on SSRIs have poorer responses — the STAR*D trial demonstrated that l-methylfolate augmentation (Deplin 15mg) improved SSRI response rates by 18.5% in treatment-resistant depression (Papakostas 2012).
- Melatonin: SSRIs increase synaptic serotonin availability, but this may shunt tryptophan away from the melatonin pathway. Sleep disruption is one of the most common SSRI side effects. Melatonin 0.5-3mg at bedtime often resolves this.
- Sodium: SSRI-induced hyponatremia (SIADH) is a recognized adverse effect, particularly in elderly patients. Monitor sodium in the first month and with any symptoms of confusion, nausea, or headache.
- Bone density: Serotonin receptors exist on osteoblasts and osteoclasts. SSRIs have been associated with reduced bone mineral density and increased fracture risk (Haney 2007). Monitor DEXA in long-term SSRI users.
NSAIDs
Drugs: Ibuprofen, naproxen, diclofenac, celecoxib, aspirin
Nutrient depletions:
- Iron: GI mucosal erosion and occult bleeding is the most common cause of iron depletion from NSAIDs. Even low-dose aspirin causes measurable GI blood loss.
- Folate: NSAIDs may impair folate absorption and metabolism.
- Vitamin C: Increased oxidative stress and GI lining damage increases vitamin C utilization.
- Gut barrier integrity: NSAIDs increase intestinal permeability (“leaky gut”) by inhibiting COX-1 prostaglandins that maintain the mucosal barrier. This is not a nutrient per se, but it is a critical functional depletion with systemic consequences.
Clinical protocol: Monitor ferritin in chronic NSAID users. Supplement vitamin C 500-1000mg, folate 400mcg. Consider gut-protective strategies: zinc carnosine 75mg twice daily, L-glutamine 5g, DGL licorice, and ultimately address the root cause of pain to reduce NSAID dependence.
Anticonvulsants
Drugs: Phenytoin (Dilantin), carbamazepine (Tegretol), valproic acid (Depakote), phenobarbital, lamotrigine
Nutrient depletions:
- Folate: Most anticonvulsants impair folate absorption or increase catabolism. Critical in women of childbearing age — neural tube defect risk is elevated in epileptic women on anticonvulsants.
- Vitamin D and Calcium: Anticonvulsants induce CYP450 enzymes that accelerate vitamin D catabolism. Osteomalacia and osteoporosis risk increases significantly with long-term use.
- Carnitine: Valproic acid depletes carnitine through urinary excretion of valproylcarnitine. Can cause hyperammonemia and hepatotoxicity. Carnitine supplementation (30mg/kg/day) is recommended by many neurologists.
- Biotin: Carbamazepine and phenytoin increase biotin catabolism.
Clinical protocol: Methylfolate 1-2mg (critical, especially for women), vitamin D 2000-5000 IU with calcium citrate and K2, carnitine 500-1000mg (especially with valproate), B-complex including biotin. DEXA monitoring.
Additional Medications
ACE Inhibitors (lisinopril, enalapril, ramipril)
Zinc depletion: ACE inhibitors chelate zinc as part of their mechanism (ACE is a zinc-dependent metalloenzyme). Early symptom: taste changes (dysgeusia). Supplement zinc 15-30mg.
Beta-Blockers (metoprolol, atenolol, propranolol)
CoQ10 depletion: Beta-blockers inhibit CoQ10-dependent enzymes. Supplement 100mg. Melatonin suppression: Beta-blockers block beta-1 adrenergic receptors in the pineal gland, reducing melatonin synthesis. This explains the insomnia commonly reported with beta-blockers. Melatonin 0.5-3mg at bedtime resolves this.
Thyroid Medication (Levothyroxine)
Not a nutrient depletion per se, but critical timing separations are required because multiple nutrients block levothyroxine absorption:
- Calcium: 4-hour separation
- Iron: 4-hour separation
- Magnesium: 4-hour separation
- Coffee: 1-hour separation (Benvenga 2008 — coffee reduced levothyroxine absorption by up to 36%)
- Take levothyroxine on an empty stomach, first thing in the morning, with water only. Wait 30-60 minutes before eating or drinking anything else.
The Clinical Protocol: Universal Application
Every functional medicine intake should include a thorough medication review with systematic identification of nutrient depletions.
Step 1: List all current medications (including OTC, PPIs, antacids, NSAIDs). Step 2: Cross-reference each medication against known depletions (this reference or Mytavin/Drug-Nutrient Interactions databases). Step 3: Identify overlapping depletions — a patient on a PPI + metformin + statin is being triply depleted. Step 4: Order targeted testing: B12/MMA, RBC magnesium, ferritin panel, vitamin D, CoQ10 levels, homocysteine, folate. Step 5: Supplement specifically for identified depletions using bioavailable forms. Step 6: Recheck levels in 3-6 months. Step 7: Address root causes to reduce medication burden where possible.
The medications serve a purpose. The nutrient depletions are the unintended cost. A skilled clinician manages both — supporting the therapeutic goal while preventing the biochemical collateral damage.
What nutrient depletions are hiding in your medicine cabinet right now?