Phenobarbital, Phenytoin & Nutrient Depletion
Also searched as Dilantin with PB. What the clinical evidence reports, what it may mean, and what to discuss with your pharmacist.
Phenobarbital, Phenytoin has been associated with depletion of ACETYL-L-CARNITINE, L-CARNITINE, PROPIONYL-L-CARNITINE and VITAMIN K and 10 more. This does not mean a deficiency will occur — it means these are worth knowing about and, if you take Phenobarbital, Phenytoin long-term, worth raising with your pharmacist or healthcare provider.
Take more than one medication? Open the checker with Phenobarbital, Phenytoin pre-loaded and add the rest to see overlapping nutrient signals.
Reported nutrient depletions with Phenobarbital, Phenytoin
Each record below is shown as published in our licensed clinical database, with its evidence rating and citations. Expand a section for food sources and talking points.
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ACETYL-L-CARNITINE
Insignificant DepletionPHENYTOIN (Dilantin)
Data on the effect of phenytoin on blood levels of carnitines are conflicting. Some studies have found reduced levels in some patients on phenytoin. However, other studies have found no effect. Routine L-carnitine or acetyl-L-carnitine supplementation does not seem to be necessary.
Acetyl-L-carnitine is a compound your body uses to help turn fat into energy and support nerve cell function. Research on whether phenytoin actually lowers it in the blood is mixed, with some studies showing a modest reduction and others finding no change at all. Given that the evidence is conflicting and the rating here is insignificant, most people on phenytoin or phenobarbital do not need to worry about this or take a supplement. If you have concerns, it is always worth a quick conversation with your pharmacist or doctor.
Learn more about this nutrient: Acetyl-l-carnitine — uses, safety & interactions
References (3)
- Hug G, McGraw CA, Bates SR, et al. Reduction of serum carnitine concentrations during anticonvulsant therapy with phenobarbital, valproic acid, phenytoin, and carbamazepine in children. J Pediatr 1991;119:799-802. PubMed
- De Vivo DC, Bohan TP, Coulter DL, et al. L-carnitine supplementation in childhood epilepsy: Current perspectives. Epilepsia 1998;39:1216-25.
- Opala G, Winter S, Vance C, et al. The effect of valproic acid on plasma carnitine levels. Am J Dis Child 1991;145:999-1001. PubMed
L-CARNITINE
Insignificant DepletionPHENOBARBITAL (Luminal)
Some studies have found reduced levels of L-carnitine in some patients taking phenobarbital. However, other studies have found no significant effect. Routine L-carnitine supplementation does not seem to be necessary.
L-carnitine is a compound your body uses to convert fat into energy, and it plays a supporting role in muscle and nerve function. Some research has found lower carnitine levels in people taking phenobarbital, possibly because the drug speeds up certain liver enzymes that affect how carnitine is processed, but other studies have seen no real difference at all. Given the mixed evidence and an insignificant depletion rating, most people on phenobarbital do not need to worry about this or take a supplement. If you have been on this medication long-term and have questions, it is worth a quick conversation with your pharmacist or doctor.
What Carnitine does & food sources
Carnitine shuttles fatty acids into cells' mitochondria so they can be burned for energy.
Common food sources:
- Red meat (the richest source)
- Poultry and fish
- Dairy products
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What to discuss with your clinician
Carnitine questions come up with specific medications (for example, valproic acid) and specific situations — this is a conversation for your prescriber, who can weigh testing or supplementation.
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Supplement considerations
Carnitine supplements are usually reserved for clinician-identified situations rather than general use.
Do not start or stop medications or supplements without professional guidance — supplements can interact with prescription medications.
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Learn more about this nutrient: L-carnitine — uses, safety & interactions
References (5)
- Hug G, McGraw CA, Bates SR, et al. Reduction of serum carnitine concentrations during anticonvulsant therapy with phenobarbital, valproic acid, phenytoin, and carbamazepine in children. J Pediatr 1991;119:799-802. PubMed
- Castro-Gago M, Eiris-Punal J, Novo-Rodriguez MI, et al. Serum carnitine levels in epileptic children before and during treatment with valproic acid, carbamazepine, and phenobarbital. J Child Neurol 1998;13:546-9. PubMed
- Thom H, Carter PE, Cole GF, et al. Ammonia and carnitine concentrations in children treated with sodium valproate compared with other anticonvulsant drugs. Dev Med Child Neurol 1991;33:795-802. PubMed
- Zelnik N, Fridkis I, Gruener N. Reduced carnitine and antiepileptic drugs: cause relationship or co-existence? Acta Paediatr 1995;84:93-5. PubMed
- Opala G, Winter S, Vance C, et al. The effect of valproic acid on plasma carnitine levels. Am J Dis Child 1991;145:999-1001. PubMed
PROPIONYL-L-CARNITINE
Insignificant DepletionPHENOBARBITAL (Luminal)
Data on the effect of phenobarbital on blood levels of carnitines are conflicting. Some studies have found reduced levels in some patients taking phenobarbital. However, other studies have found no significant effect. Routine L-carnitine or propionyl-L-carnitine supplementation does not seem to be necessary.
Propionyl-L-carnitine is a compound your body makes naturally that helps cells convert fat into usable energy, particularly in muscle tissue. Some early studies noticed that phenobarbital users occasionally had lower carnitine levels, possibly because the drug affects how the liver processes certain compounds, but other studies found no difference at all. Given how mixed the evidence is, this is considered an insignificant concern for most people, and routine supplementation is not recommended. If you have been on phenobarbital long-term and are curious, it is worth a quick conversation with your pharmacist or doctor.
Learn more about this nutrient: Propionyl-l-carnitine — uses, safety & interactions
References (5)
- Hug G, McGraw CA, Bates SR, et al. Reduction of serum carnitine concentrations during anticonvulsant therapy with phenobarbital, valproic acid, phenytoin, and carbamazepine in children. J Pediatr 1991;119:799-802. PubMed
- Castro-Gago M, Eiris-Punal J, Novo-Rodriguez MI, et al. Serum carnitine levels in epileptic children before and during treatment with valproic acid, carbamazepine, and phenobarbital. J Child Neurol 1998;13:546-9. PubMed
- Thom H, Carter PE, Cole GF, et al. Ammonia and carnitine concentrations in children treated with sodium valproate compared with other anticonvulsant drugs. Dev Med Child Neurol 1991;33:795-802. PubMed
- Zelnik N, Fridkis I, Gruener N. Reduced carnitine and antiepileptic drugs: cause relationship or co-existence? Acta Paediatr 1995;84:93-5. PubMed
- Opala G, Winter S, Vance C, et al. The effect of valproic acid on plasma carnitine levels. Am J Dis Child 1991;145:999-1001. PubMed
VITAMIN K
Insignificant DepletionANTICONVULSANTS
When taken during pregnancy, anticonvulsants that induce hepatic enzymes (e.g., phenobarbital, phenytoin, carbamazepine) can reduce vitamin K levels in the fetus and increase the risk of intracranial hemorrhage soon after birth. It's thought that liver enzyme induction by these drugs increases vitamin K metabolism. This has a significant effect on vitamin K levels in infants, who haven't built up stores of the vitamin. When anticonvulsants are needed during pregnancy, vitamin K 10-20 mg daily should be taken orally for the last month of pregnancy, and the baby should receive vitamin K immediately after delivery. There is also limited evidence that chronic carbamazepine or phenytoin therapy can cause subclinical reductions in vitamin K activity in adults. There are rare reports of prolonged clotting times and bleeding in people with additional risk factors for vitamin K deficiency, such as poor nutritional intake. These anticonvulsants don't significantly affect vitamin K and clotting parameters in most children and adults. For information on foods that are rich in vitamin K, see our chart.
Vitamin K is something your body needs to clot blood properly and keep bones healthy. Phenobarbital and phenytoin can ramp up liver enzymes, and those enzymes then break down vitamin K faster than usual, potentially nudging levels a bit lower. For most adults on these medications, though, this effect is considered insignificant and a supplement is not typically needed. The one situation that carries real concern is pregnancy, where the impact on a newborn can be more serious, so anyone who is pregnant or planning to become pregnant while taking these medications should bring it up with their doctor right away.
What Vitamin K does & food sources
Vitamin K is required for normal blood clotting and contributes to bone health.
Common food sources:
- Leafy green vegetables (spinach, kale, broccoli)
- Vegetable oils
- Fermented foods like natto
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What to discuss with your clinician
If you take warfarin, vitamin K intake is a central part of your therapy — consistency matters more than avoidance. Discuss any planned change in vitamin K intake (diet or supplements) with the clinic that manages your INR.
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Supplement considerations
Never start or stop a vitamin K supplement on your own if you take warfarin — it directly changes how the medication works.
Do not start or stop medications or supplements without professional guidance — supplements can interact with prescription medications.
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Caution: Vitamin K interacts with warfarin: keep intake consistent and involve your anticoagulation clinic in any change.
Learn more about this nutrient: Vitamin K — uses, safety & interactions
References (8)
- Cornelissen M, Steegers-Theunissen R, Kollee L, et al. Increased incidence of neonatal vitamin K deficiency resulting from maternal anticonvulsant therapy. Am J Obstet Gynecol 1993;168:923-8. PubMed
- Cornelissen M, Steegers-Theunissen R, Kollee L, et al. Supplementation of vitamin K in pregnant women receiving anticonvulsant therapy prevents neonatal vitamin K deficiency. Am J Obstet Gynecol 1993;168:884-8. PubMed
- Renzulli P, Tuchschmid P, Eich G, et al. Early vitamin K deficiency bleeding after maternal phenobarbital intake: management of massive intracranial haemorrhage by minimal surgical intervention. Eur J Pediatr 1998;157:663-5. PubMed
- Bleyer WA, Skinner AL. Fatal neonatal hemorrhage after maternal anticonvulsant therapy. JAMA 1976;235:626-7. DOI
- Thorp JA, Gaston L, Caspers DR, Pal ML. Current concepts and controversies in the use of vitamin K. Drugs 1995;49:376-87. PubMed
- Davies VA, Rothberg AD, Argent AC, Atkinson PM, Staub H, Pienaar NL. Precursor prothrombin status in patients receiving anticonvulsant drugs. Lancet 1985;1:126-8. PubMed
- Keith DA, Gundberg CM, Japour A, et al. Vitamin K-dependent proteins and anticonvulsant medication. Clin Pharmacol Ther 1983;34:529-32. PubMed
- Tam DA Jr, Myer EC. Vitamin K-dependent coagulopathy in a child receiving anticonvulsant therapy. J Child Neurol 1996;11:244-6. PubMed
ZINC
Insignificant DepletionPHENYTOIN (Dilantin)
Phenytoin can chelate zinc in vitro and has been associated with both reduced and increased zinc absorption in animals. Although there are occasional case reports of reduced serum zinc levels in people taking phenytoin, studies have not found a consistent reduction. Routine zinc supplements are not necessary with phenytoin.
Zinc is a mineral your body uses for immune function, wound healing, and keeping enzymes working properly. Phenytoin has been shown in some studies to increase how much zinc the kidneys excrete, and it may also interfere with zinc binding in the body, though results across studies have been inconsistent. The good news is that this is rated as an insignificant depletion, meaning a routine zinc supplement is not considered necessary for most people on this medication. If you have any concerns, a quick chat with your pharmacist or doctor can help put your mind at ease.
What Zinc does & food sources
Zinc supports immune function, wound healing, taste and smell, and many enzyme systems.
Common food sources:
- Meat and shellfish (especially oysters)
- Beans and lentils
- Nuts and seeds
- Whole grains
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What to discuss with your clinician
Ask about zinc status if you take an associated medication long-term and notice slow wound healing, frequent infections, or taste changes — a clinician can decide whether testing or an empiric plan makes sense.
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Supplement considerations
Zinc competes with copper for absorption — long-term, higher-dose zinc without medical guidance can cause copper deficiency. Zinc also binds some antibiotics in the gut, so dose timing matters.
Do not start or stop medications or supplements without professional guidance — supplements can interact with prescription medications.
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Caution: Keep zinc doses moderate and time them away from interacting medications — ask your pharmacist.
Learn more about this nutrient: Zinc — uses, safety & interactions
References (6)
- Weismann K. Chelating drugs and zinc. Dan Med Bull 1986;33:208-11.
- Palm R, Hallmans G. Zinc and copper metabolism in phenytoin therapy. Epilepsia 1982;23:453-61. PubMed
- Higashi A, Ikeda T, Matsukura M, Matsuda I. Serum zinc and vitamin E concentrations in handicapped children treated with anticonvulsants. Devel Pharmacol Ther 1982;5:109-13. DOI
- Akram M, Sullivan C, Mack G, Buchannan N. What is the clinical significance of reduced manganese and zinc levels in treated epileptic patients? Med J Australia 1989;15:113. PubMed
- Ilhan A, Uz E, Kali S, et al. Serum and hair trace element levels in patients with epilepsy and healthy subjects: does the antiepileptic therapy affect the element concentrations of hair? Eur J Neurol 1999;6:705-9. PubMed
- Liu CS, Wu HM, Kao SH, Wei YH. Serum trace elements, glutathione, copper/zinc superoxide dismutase, and lipid peroxidation in epileptic patients with phenytoin or carbamazepine monotherapy. Clin Neuropharmacol 1998;21:62.
BIOTIN
Moderate DepletionPHENOBARBITAL (Luminal)
Reduced plasma biotin levels can occur in people taking phenobarbital. In one study, plasma levels were 50% lower in people taking phenobarbital or various other anticonvulsants than in controls. There may also be increased urinary excretion of organic acids, an indicator of reduced biotin-dependent enzyme activity. Suggested mechanisms include competitive inhibition of biotin transport in the intestine, increased catabolism of biotin, and decreased renal tubular reabsorption of biotin. Phenobarbital contains a carbamide group, which is also present in biotin, and may lead to competition for intestinal and renal tubular absorption sites. The clinical significance of these effects on biotin isn't clear.
Biotin is a B vitamin your body uses to convert food into energy and keep your skin, hair, and nervous system working properly. Phenobarbital appears to interfere with biotin on a few fronts at once: it may compete with biotin for absorption in the gut, speed up how quickly the body breaks it down, and reduce how much the kidneys hold onto rather than flush out in urine. Research has found blood biotin levels noticeably lower in people taking this type of seizure medication, so this is worth paying attention to for long-term users. If you have been on phenobarbital for a while, it is a good idea to ask your pharmacist or doctor whether checking your biotin status makes sense for you.
Learn more about this nutrient: Biotin — uses, safety & interactions
References (7)
- Krause KH, Bonjour JP, Berlit P, Kochen W. Biotin status of epileptics. Ann N Y Acad Sci 1985;447:297-313.
- Krause KH, Kochen W, Berlit P, Bonjour JP. Excretion of organic acids associated with biotin deficiency in chronic anticonvulsant therapy. Int J Vitam Nutr Res 1984;54:217-22.
- Krause KH, Berlit P, Bonjour JP. Vitamin status in patients on chronic anticonvulsant therapy. Int J Vitam Nutr Res 1982;52:375-85.
- Mock DM, Dyken ME. Biotin deficiency results from long-term therapy with anticonvulsants (abstract). Gastroenterology 1995;108:A740. DOI
- Mock DM, Mock NI, Nelson RP, Lombard KA. Disturbances in biotin metabolism in children undergoing long-term anticonvulsant therapy. J Pediatr Gastroentereol Nutr 1998;26:245-50.
- Mock DM, Dyken ME. Biotin catabolism is accelerated in adults receiving long-term therapy with anticonvulsants. Neurology 1997;49:1444-7. PubMed
- Rathman SC, Eisenschenk S, McMahon RJ. The abundance and function of biotin-dependent enzymes are reduced in rats chronically administered carbamazepine. J Nutr 2002;132:3405-10. PubMed
CALCIUM
Moderate DepletionPHENOBARBITAL (Luminal)
Phenobarbital decreases calcium absorption by increasing metabolism of vitamin D, which is needed for calcium absorption. Hypocalcemia and osteomalacia have occurred, especially with prolonged therapy or when used in combination with carbamazepine and/or phenytoin. Advise patients taking phenytoin for six months or more that they may also need vitamin D and calcium supplements. For information on foods that are rich in calcium, see our chart.
Both phenobarbital and phenytoin can gradually reduce calcium levels in your body, and calcium is the mineral your bones and teeth depend on to stay strong. The main reason is a bit indirect: these medications speed up how your liver breaks down vitamin D, and without enough vitamin D your gut simply cannot absorb calcium properly from food. Because this is rated as a moderate concern, people who have been on either of these medications for six months or longer are often worth checking, and some do end up needing vitamin D and calcium supplements. It is a good conversation to have with your doctor or pharmacist, especially if you have other bone-health risk factors.
What Calcium does & food sources
Calcium builds and maintains bone and is essential for muscle contraction and nerve signaling.
Common food sources:
- Dairy products (milk, yogurt, cheese)
- Fortified plant milks and juices
- Canned fish with bones (sardines, salmon)
- Leafy greens like kale
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What to discuss with your clinician
Ask your provider whether bone health monitoring (and vitamin D testing) makes sense with long-term use of an associated medication — a blood calcium level alone does not capture bone calcium status.
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Supplement considerations
Calcium can interfere with the absorption of several medications (some antibiotics, thyroid medication, iron) — separate the doses and confirm timing with your pharmacist. Total intake from food plus supplements matters more than supplements alone.
Do not start or stop medications or supplements without professional guidance — supplements can interact with prescription medications.
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Caution: Very high calcium intake has its own risks (kidney stones in susceptible people) — more is not better.
Learn more about this nutrient: Calcium — uses, safety & interactions
References (5)
- Gough H, Goggin T, Bissessar A, et al. A comparative study of the relative influence of different anticonvulsant drugs, UV exposure and diet on vitamin D and calcium metabolism in out-patients with epilepsy. Quart J Med 1986;59:569-77. DOI
- Hoikka V, Alhava EM, Karjalainen P, et al. Carbamazepine and bone mineral metabolism. Acta Neurol Scand 1984;70:77-80. PubMed
- Rajantie J, Lamberg-Allardt C, Wilska M. Does carbamazepine treatment lead to a need of extra vitamin D in some mentally retarded children? Acta Paediatr Scand 1984;73:325-8. PubMed
- Bell RD, Pak CY, Zerwekh J, et al. Effect of phenytoin on bone and mineral density in ambulatory epileptic children. Brain Dev 1994;16:382-5.
- Collins N, Maher J, Cole M, et al. A prospective study to evaluate the dose of vitamin D required to correct low 25-hydroxyvitamin D levels, calcium, and alkaline phosphatase in patients at risk of developing antiepileptic drug-induced osteomalacia. Q J M
FOLIC ACID
Moderate DepletionPHENYTOIN (Dilantin)
Phenytoin can reduce serum folate levels, occasionally leading to megaloblastic anemia, and possibly contributing to neurological side effects and mental changes. Population research has found that taking phenytoin for over two years is associated with a reduction in folate levels and an approximately 6-fold increase in risk for folate deficiency when compared with taking phenytoin for less than one year. Possible mechanisms include reduced folic acid absorption, increased metabolism, increased demand for folic acid as a coenzyme for induced hepatic enzymes, or competitive interaction between folate coenzymes and phenytoin. Folic acid supplements may reduce phenytoin side effects. Pregnant patients taking phenytoin may be especially at risk from reduced folate levels, as low folate levels during pregnancy may contribute to birth defects and pregnancy loss. However, folic acid can reduce phenytoin serum levels and increase seizure frequency. Advise patients taking phenytoin chronically to consult their physician before taking folic acid supplements. For information on foods that are rich in folate, see our chart.
Folate is a B vitamin your body uses to build healthy red blood cells and support normal nerve function, and long-term use of phenytoin or phenobarbital has been linked to meaningfully lower folate levels in some patients. These seizure medications appear to interfere with how the gut absorbs folate and may also speed up the liver's breakdown of it, leaving less available in the bloodstream over time. This is rated a moderate concern, meaning it does not affect everyone but is worth paying attention to, especially for people who have been on these medications for years. Talk with your pharmacist or doctor before adding a folate supplement, because folic acid can actually affect how well these medications control seizures.
What Folic acid (folate) does & food sources
Folate is needed for cell division, red blood cell formation, and healthy fetal development.
Common food sources:
- Leafy green vegetables
- Beans, lentils, and peas
- Fortified grains and cereals
- Citrus fruits
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
What to discuss with your clinician
Ask your provider whether folate monitoring or supplementation is appropriate for you — this matters most before and during pregnancy, and with long-term use of certain seizure or arthritis medications.
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Supplement considerations
Folate needs are individual. With some medications (for example, methotrexate), folic acid is often prescribed deliberately on a specific schedule — follow your prescriber's instructions rather than adding your own.
Do not start or stop medications or supplements without professional guidance — supplements can interact with prescription medications.
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
Caution: High-dose folic acid can mask vitamin B12 deficiency, so the two are often evaluated together.
Learn more about this nutrient: Folic Acid — uses, safety & interactions
References (11)
- Froscher W, Maier V, Laage M, et al. Folate deficiency, anticonvulsant drugs, and psychiatric morbidity. Clin Neuropharmacol 1995;18:165-82. PubMed
- Lambie DG, Johnson RH. Drugs and folate metabolism. Drugs 1985;30:145-55. PubMed
- Reynolds EH. Neurological aspects of folate and vitamin B12 metabolism. Clin Haematol 1976;5:661-96. DOI
- Reynolds EH. Folate metabolism and anticonvulsant therapy. Proc R Soc Med 1974;67:68.
- Reynolds EH, Trimble MR. Adverse neuropsychiatric effects of anticonvulsant drugs. Drugs 1985;29:570-81. PubMed
- Kathiravan M, Kavitha S, Shanthi R. To determine the effect of long-term antiepileptic drug on the serum folate and vitamin B12 among epileptic patients. Sci Rep 2021;11(1):4393. PubMed
- Lewis DP, Van Dyke DC, Willhite LA, et al. Phenytoin-folic acid interaction. Ann Pharmacother 1995;29:726-35. PubMed
- Shafer RB, Nuttall FQ. Calcium and folic acid absorption in patients taking anticonvulsant drugs. J Clin Endocrinol Metab 1975;41:1125-9. PubMed
- Hiilesmaa VK, Teramo K, Granstrom ML, Bardy AH. Serum folate concentrations during pregnancy in women with epilepsy: relation to antiepileptic drug concentrations, number of seizures, and fetal outcome. Br Med J 1983;287:577-9. DOI
- Dansky LV, Rosenblatt DS, Andermann E. Mechanisms of teratogenesis: folic acid and antiepileptic therapy. Neurology 1992;42:32-42.
- Lewis DP, Van Dyke DC, Stumbo PJ, Berg MJ. Drug and environmental factors associated with adverse pregnancy outcomes. Part I: antiepileptic drugs, contraceptives, smoking, and folate. Ann Pharmacother 1998;32:802-17. PubMed
NIACIN
Moderate DepletionPHENYTOIN (Dilantin)
Case reports describe symptoms consistent with pellagra in people taking phenytoin alone or in combination with other anticonvulsants; however, the mechanism is not known.
Niacin is a B vitamin your body uses for energy production, healthy skin, and nerve function. People taking phenytoin, sometimes alongside other seizure medicines like phenobarbital, have been reported in medical literature to develop signs of niacin deficiency, though exactly why this happens is not yet fully understood. Because this is rated as a moderate concern, longer-term users have a real reason to bring it up with their pharmacist or doctor, who can check whether any monitoring or supplementation makes sense for them personally.
What Vitamin B3 (niacin) does & food sources
Niacin supports energy metabolism, skin health, and nervous system function.
Common food sources:
- Poultry, beef, and fish
- Peanuts and legumes
- Fortified grains
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
What to discuss with your clinician
Deficiency is rare in a typical diet. Discuss with your provider before using niacin as a supplement — at pharmacologic doses it behaves like a medication.
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Supplement considerations
High-dose niacin causes flushing and can affect the liver, blood sugar, and uric acid — it is not a casual supplement.
Do not start or stop medications or supplements without professional guidance — supplements can interact with prescription medications.
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Caution: Treat high-dose niacin as a medication decision, not a nutrition one.
Learn more about this nutrient: Niacin — uses, safety & interactions
VITAMIN B12
Moderate DepletionPHENOBARBITAL (Luminal)
In one case report, a 23-year-old male with epilepsy who was taking phenytoin with phenobarbital for two years presented with megaloblastic anemia due to severe decreases in vitamin B12 and folate levels. Theoretically, phenytoin and/or phenobarbital may have interfered with vitamin B12 absorption. Encourage patients to maintain adequate dietary vitamin B12 intake, and check folate and vitamin B12 status if symptoms of anemia develop. If considering alternatives, neither oxcarbazepine (Trileptal), levetiracetam (Keppra), nor valproate have been associated with reduced vitamin B12 levels. For information on foods that are rich in vitamin B12, see our chart.
Vitamin B12 is something your nerves and red blood cells genuinely depend on, so it is worth keeping an eye on when taking phenobarbital or phenytoin long-term. These seizure medications may interfere with how well your gut absorbs B12, though the exact reason is not fully understood. This is rated a moderate concern, meaning deficiency does not happen to everyone but is real enough that some long-term users do need a supplement. If you notice unusual tiredness or have been on these medications for years, it is a good idea to ask your doctor or pharmacist about checking your B12 and folate levels.
What Vitamin B12 does & food sources
Vitamin B12 supports red blood cell formation, nerve function, and DNA synthesis.
Common food sources:
- Meat, poultry, and fish
- Eggs and dairy products
- Fortified cereals and nutritional yeast
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What to discuss with your clinician
If you take an associated medication long-term, ask your healthcare provider whether checking a vitamin B12 level (sometimes with methylmalonic acid) is appropriate — especially if you notice fatigue, numbness, tingling, or memory changes.
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Supplement considerations
B12 status is easy to check and low levels are usually straightforward to address, so testing before supplementing is often the sensible order. High-dose folic acid can mask a B12 deficiency, which is one reason B12 and folate questions are best sorted out together with your provider.
Do not start or stop medications or supplements without professional guidance — supplements can interact with prescription medications.
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
Caution: B12 deficiency can look like other conditions — do not self-diagnose from symptoms alone.
Learn more about this nutrient: Vitamin B12 — uses, safety & interactions
References (5)
- Reynolds EH, Hallpike JF, Phillips BM, et al. Reversible absorptive defects in anticonvulsant megaloblastic anemia. J Clin Pathol 1965;18:593-8.
- Rezaei S, Shab-Bidar S, Abdurahman AA, Djafarian K. Oxcarbazepine administration and the serum levels of homocysteine, vitamin B12 and folate in epileptic patients: A systematic review and meta-analysis. Seizure. 2017;45:87-94. PubMed
- Sharma TK, Vardey SK, Sitaraman S. Evaluate the Effect of Valproate Monotherapy on the Serum Homocysteine, Folate and Vitamin B12 Levels in Epileptic Children. Clin Lab. 2015;61(8):933-40. PubMed
- Mahdavi A, Naeini AA, Najafi M, Ghazvini M, Maracy M. Vitamin B12 and Folate Status in Patients with Epilepsy Under Levetiracetam Monotherapy. Int J Prev Med. 2019;10:32. PubMed
- Ozdemir O, Yakut A, Dinleyici EC, Aydogdu SD, Yarar C, Colak O. Serum asymmetric dimethylarginine (ADMA), homocysteine, vitamin B(12), folate levels, and lipid profiles in epileptic children treated with valproic acid. Eur J Pediatr. 2011;170(7):873-7.
VITAMIN D
Moderate DepletionPHENYTOIN (Dilantin)
Phenytoin increases hepatic metabolism of vitamin D to inactive compounds, thereby reducing calcium absorption. Hypocalcemia and osteomalacia have occurred, especially with prolonged therapy, concurrent use of other enzyme-inducing anticonvulsants, or when other risk factors for vitamin D deficiency are present. Patients taking phenytoin for 6 months or more may need vitamin D and calcium supplements. Doses of vitamin D needed vary from 400-4000 IU daily. For information on foods that are rich in vitamin D, see our chart.
Phenytoin and phenobarbital are both processed by the liver, and that processing can actually speed up the breakdown of vitamin D, which your bones and muscles depend on to absorb calcium properly. Over time, lower vitamin D levels can leave your bones weaker than they should be, and this concern is real enough that some long-term users genuinely do need a supplement. If you have been taking either of these medications for six months or more, it is worth having a conversation with your pharmacist or doctor about checking your vitamin D status.
What Vitamin D does & food sources
Vitamin D helps the body absorb calcium and supports bone, muscle, and immune health.
Common food sources:
- Fatty fish (salmon, mackerel)
- Fortified milk and cereals
- Egg yolks
- Sunlight exposure (the main natural source)
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
What to discuss with your clinician
A 25-hydroxyvitamin D blood test is the standard way to assess status — ask whether it is appropriate if you take an associated medication long-term, have limited sun exposure, or have bone concerns.
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
Supplement considerations
Vitamin D dosing varies a lot between people; some medications change how vitamin D is processed. Your provider can target a dose to your level instead of guessing.
Do not start or stop medications or supplements without professional guidance — supplements can interact with prescription medications.
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
Caution: Vitamin D is fat-soluble and can accumulate — very high doses over time can cause harm, so follow a clinician-guided plan.
Learn more about this nutrient: Vitamin D — uses, safety & interactions
References (5)
- Gough H, Goggin T, Bissessar A, et al. A comparative study of the relative influence of different anticonvulsant drugs, UV exposure and diet on vitamin D and calcium metabolism in out-patients with epilepsy. Quart J Med 1986;59:569-77. DOI
- Hoikka V, Alhava EM, Karjalainen P, et al. Carbamazepine and bone mineral metabolism. Acta Neurol Scand 1984;70:77-80. PubMed
- Rajantie J, Lamberg-Allardt C, Wilska M. Does carbamazepine treatment lead to a need of extra vitamin D in some mentally retarded children? Acta Paediatr Scand 1984;73:325-8. PubMed
- Bell RD, Pak CY, Zerwekh J, et al. Effect of phenytoin on bone and mineral density in ambulatory epileptic children. Brain Dev 1994;16:382-5.
- Collins N, Maher J, Cole M, et al. A prospective study to evaluate the dose of vitamin D required to correct low 25-hydroxyvitamin D levels, calcium, and alkaline phosphatase in patients at risk of developing antiepileptic drug-induced osteomalacia. Q J M
VITAMIN E
Moderate DepletionPHENYTOIN (Dilantin)
There is some evidence that children who take phenytoin have serum vitamin E levels 9% to 26% lower than children with untreated epilepsy. The clinical significance of this effect isn't clear. Vitamin E supplements don't seem to be harmful in children with epilepsy. They've been associated with either no effect on seizure control, or improved seizure control. Advise patients to maintain the recommended dietary intake of vitamin E. Consider supplements if plasma vitamin E levels are low (below 5 micrograms/mL).
Vitamin E is an antioxidant your body uses to protect cells and support immune function, and there is some evidence that phenytoin in particular may lower blood levels of it, possibly because these medications affect how the liver processes fat-soluble vitamins. Studies in children taking phenytoin have found levels noticeably lower than in untreated peers, though what that means clinically is still not fully understood. This is rated moderate, so it is worth keeping on your radar, especially for longer-term users. Ask your pharmacist or doctor whether checking your vitamin E level makes sense for you, and focus on getting plenty of vitamin E through food in the meantime.
What Vitamin E does & food sources
Vitamin E is a fat-soluble antioxidant that protects cell membranes.
Common food sources:
- Vegetable oils
- Nuts and seeds
- Wheat germ
- Leafy greens
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
What to discuss with your clinician
Deficiency is rare; ask your provider before supplementing, particularly if you take blood thinners.
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
Supplement considerations
Higher-dose vitamin E can increase bleeding tendency, especially with warfarin or antiplatelet medications.
Do not start or stop medications or supplements without professional guidance — supplements can interact with prescription medications.
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
Caution: Discuss vitamin E supplements with your provider if you take any blood thinner.
Learn more about this nutrient: Vitamin E — uses, safety & interactions
References (6)
- Ogunmekan AO. Relationship between age and vitamin E level in epileptic children and normal children. Am J Clin Nutr 1979;32:2269-71.
- Kataoka K, Kanamori N, Oishi M, et al. Vitamin E status in pediatric patients receiving antiepileptic drugs. Devel Pharmacol Ther 1989;14:96-101. DOI
- Ogunmekan AO. Plasma vitamin E (alpha-tocopherol) levels in normal children and in epileptic children with and without anticonvulsant drug therapy. Trop Geog Med 1985;37:175-7.
- Higashi A, Ikeda T, Matsukura M, Matsuda I. Serum zinc and vitamin E concentrations in handicapped children treated with anticonvulsants. Devel Pharmacol Ther 1982;5:109-13. DOI
- Higashi A, Tamari H, Ikeda T, et al. Serum vitamin E concentration in patients with severe multiple handicaps treated with anticonvulsants. Pediatr Pharmacol 1980;1:129-34.
- Ogunmekan AO, Hwang PA. A randomized, double-blind, placebo-controlled, clinical trial of D-alpha-tocopheryl acetate (vitamin E), as add-on therapy, for epilepsy in children. Epilepsia 1989;30:84-9.
RIBOFLAVIN
Insufficient EvidencePHENOBARBITAL (Luminal)
Some evidence in animals suggests that phenobarbital induces metabolism of riboflavin in the liver. Levels of the active form of riboflavin, flavin adenine dinucleotide (FAD), are increased in the liver and levels of a hydroxylated metabolite are increased in the urine. Also, some animal research suggests that phenobarbital does not significantly affect the content of flavin in the liver.
Riboflavin, which your body uses to convert food into energy and keep tissues healthy, may be processed differently in the liver when you take phenobarbital. Some animal studies suggest phenobarbital speeds up how the liver handles riboflavin, potentially shifting its active form. That said, the research is limited and conflicting, so the real-world impact on people is simply not known yet. If you have been on these medications long-term and have concerns, it is worth a quick conversation with your pharmacist or doctor.
What Vitamin B2 (riboflavin) does & food sources
Riboflavin helps the body produce energy and process other B vitamins.
Common food sources:
- Dairy products and eggs
- Lean meats
- Fortified grains
- Green vegetables
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
What to discuss with your clinician
Deficiency is uncommon with a varied diet; ask your provider if you have persistent mouth-corner cracking, sore tongue, or unexplained fatigue on a long-term associated medication.
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Supplement considerations
Riboflavin is water-soluble and excess is excreted (it turns urine bright yellow — harmless).
Do not start or stop medications or supplements without professional guidance — supplements can interact with prescription medications.
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
Learn more about this nutrient: Riboflavin — uses, safety & interactions
References (3)
- Ohkawa H, Ohishi N, Yagi K. Hydroxylation of the 7- and 8-methyl groups of riboflavin by the microsomal electron transfer system of rat liver. J Biol Chem 1983;258:5629-33.. DOI
- Hamajima S, Ono S, Hirano H, Obara K. Induction of the FAD synthetase system in rat liver by phenobarbital administration. Int J Vit Nutr Res 1979;49:59-63..
- Shargel L, Mazel P. Effect of riboflavin deficiency on phenobarbital and 3-methylcholanthrene induction of microsomal drug-metabolizing enzymes of the rat. Biochem Pharmacol. 1973;22(19):2365-73. PubMed
THIAMINE
Insufficient EvidencePHENYTOIN (Dilantin)
Some evidence suggests that chronic treatment with phenytoin might reduce levels of thiamine in plasma and cerebrospinal fluid, and reduce uptake of thiamine into nerve tissue. Theoretically, this could contribute to side effects of phenytoin such as polyneuropathy and cerebellar ataxia. However, it isn't clear whether affected patients also had other factors contributing to thiamine deficiency, such as dietary insufficiency. There isn't enough evidence to recommend routine thiamine supplementation.
Thiamine is a B vitamin your nerves and brain depend on to work properly. Some research hints that phenytoin may interfere with how nerve tissue takes up thiamine, which is interesting because nerve-related side effects are already known with long-term phenytoin use. That said, the evidence is quite thin, and it is not clear whether diet or other factors played a role in the cases studied. There is not enough information to suggest routine supplementation, so if you have been on phenytoin for a long time and have questions about your nutrient levels, it is worth a conversation with your pharmacist or doctor.
What Vitamin B1 (thiamine) does & food sources
Thiamine helps convert food into energy and is essential for nerve and heart function.
Common food sources:
- Whole grains and fortified cereals
- Pork
- Beans and lentils
- Nuts and seeds
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
What to discuss with your clinician
Ask about thiamine if you take an associated medication (for example, a long-term loop diuretic in heart failure) and have symptoms like fatigue or worsening heart failure control — this is an area your care team can weigh.
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
Supplement considerations
Thiamine is water-soluble and generally low-risk, but supplementing to treat a suspected problem should still be clinician-guided so the real cause is not missed.
Do not start or stop medications or supplements without professional guidance — supplements can interact with prescription medications.
HelloPharmacist pharmacist-reviewed education — separate from the licensed record above.
Learn more about this nutrient: Thiamine — uses, safety & interactions
References (3)
- Botez MI, Botez T, Ross-Chouinard A, Lalonde R. Thiamine and folate treatment of chronic epileptic patients: a controlled study with the Wechsler IQ scale. Epilepsy Res 1993;16:157-63.. PubMed
- Botez MI, Joyal C, Maag U, Bachevalier J. Cerebrospinal fluid and blood thiamine concentrations in phenytoin-treated epileptics. Can J Neurol Sci 1982;9:37-9.. PubMed
- Patrini C, Perucca E, Reggiani C, Rindi G. Effects of phenytoin on the in vivo kinetics of thiamine and its phosphoesters in rat nervous tissues. Brain Res 1993;628:179-86.. PubMed
This tool is educational and is not a substitute for professional medical advice. An association is not a diagnosis and does not mean a deficiency will occur. Always talk to your pharmacist or healthcare provider before starting, stopping, or changing any medication or supplement.
Disclaimer: This checker finds which nutrients might be depleted by prescription or over-the-counter medications. Each nutrient depletion issue is rated based on clinical significance. Use your own professional judgment prior to making clinical decisions.© 2026 Therapeutic Research Center Licensed records refresh weekly · last updated July 3, 2026.
More about Phenobarbital, Phenytoin
What drug-induced nutrient depletion means
Some medications can, over time, lower the levels of certain vitamins, minerals, or other nutrients — through reduced absorption, increased loss, or changes in how the body uses them.
Association is not deficiency
An entry here means a depletion has been reported or studied — not that it happens to everyone, or that you are deficient. Dose, duration, diet, and your own health all matter.
Evidence varies by pair
Some drug–nutrient links (like metformin and vitamin B12) are well studied; others rest on limited or preliminary research. Each entry shows the evidence rating from our licensed clinical database.
When to ask about labs
If you take an associated medication long-term, ask your healthcare provider whether monitoring is appropriate for you. Not everyone needs testing — your provider can weigh your dose, duration, and symptoms.
Don't self-supplement blindly
Supplements are not risk-free: some can interact with medications, and some (like potassium or magnesium) can be risky with kidney disease. Talk to your pharmacist before adding anything.
Never stop a medication over this
These medications are prescribed for good reasons, and the benefit usually far outweighs a manageable nutrient consideration. Any change belongs in a conversation with your prescriber.
Food first, usually
For many nutrients, a varied diet covers the gap. Each entry lists common food sources; a supplement is a decision to make with your pharmacist or provider, not a default.
Phenobarbital, Phenytoin & nutrients: FAQs
Does Phenobarbital, Phenytoin deplete ACETYL-L-CARNITINE?
Should I take a supplement because I take Phenobarbital, Phenytoin?
Should I stop taking Phenobarbital, Phenytoin?
Where does this information come from?
Questions about Phenobarbital, Phenytoin and your nutrition?
Ask a licensed pharmacist — free, no appointment needed.
Sources & How We Checked
Nutrient depletion records for Phenobarbital, Phenytoin are evidence-graded and sourced from the Natural Medicines database, and are displayed as published with their citations.
- Natural Medicines (Therapeutic Research Center) — Evidence-graded clinical reference for drug-induced nutrient depletions, supplements, and interactions — the basis for this page.
- MedlinePlus, U.S. National Library of Medicine — NIH consumer drug information, used for medication overviews across the site.
Content is written and reviewed by licensed HelloPharmacist pharmacists. See our data sources and editorial standards for how this information is built and checked.