Interaction with Dietary Supplements
One controlled study showed that long-term use of phenobarbital increases the breakdown of
biotin.1 A test tube study also showed that primidone, a drug that is converted to
phenobarbital by the body, prevents the absorption of biotin.2 Further research is
needed to determine whether people taking phenobarbital might be at risk for biotin
Individuals on long-term multiple anticonvulsant therapy may develop below-normal blood levels
of calcium, which may be related to drug-induced
vitamin D deficiency.3 Two infants born to women taking high doses of phenytoin
and phenobarbital while pregnant developed jitteriness and tetany (a syndrome characterized by
muscle twitches), cramps, and spasms that can be caused by calcium deficiency during the first
two weeks of life.4 Controlled research is needed to determine whether pregnant women who are taking anticonvulsant
medications should supplement with additional amounts of calcium and vitamin D.
One controlled study showed that taking phenobarbital resulted in reduced blood levels of
L-carnitine.5 Further research is needed to determine whether people taking
phenobarbital might benefit from supplemental L-carnitine. Based on the currently available
information, some healthcare practitioners may recommend monitoring L-carnitine blood levels
or supplementing with L-carnitine.
Long-term treatment with phenobarbital results in dramatic reductions in folic acid blood
levels, though the clinical significance of this effect is unclear.6 Nevertheless,
some healthcare practitioners might recommend supplemental folic acid to individuals taking
One preliminary study showed that pregnant
women who use anticonvulsant drugs without folic acid supplementation have an increased risk
of having a child with birth defects, such as
heart defects, cleft lip and palate, neural tube defects, and skeletal abnormalities. However,
supplementation with folic acid greatly reduces the risk.7 Consequently, some
healthcare practitioners recommend that women taking multiple anticonvulsant drugs supplement
with 5 mg of folic acid daily, for three months prior to conception and during the first
trimester, to prevent folic acid deficiency-induced birth defects.8 Other
practitioners suggest that 1 mg or less of folic acid each day is sufficient to prevent
deficiency during pregnancy.9
One well-controlled study showed that adding folic acid to multiple anticonvulsant therapy
resulted in reduced seizure frequency.10 In addition, three infants with seizures
who were unresponsive to medication experienced immediate relief following supplementation
with the active form of folic acid.11
Despite the apparent beneficial effects, some studies have indicated that as little as 0.8
mg of folic acid taken daily can increase the frequency and/or severity of
seizures.12 13 14 15 However, a recent controlled
study showed that both healthy and epileptic women taking less than 1 mg of folic acid per day
had no increased risk for seizures.16 Until more is known about the risks and
benefits of folic acid, individuals taking multiple anticonvulsant drugs should consult with
their healthcare practitioner before supplementing with folic acid. In addition, pregnant
women or women who might become pregnant while taking anticonvulsant drugs should discuss
folic acid supplementation with their practitioner.
Anticonvulsant drugs can occasionally cause birth
defects when taken by pregnant women, and
their toxicity might be related to low blood levels of vitamin A. One controlled study showed
that taking multiple anticonvulsant drugs results in dramatic changes in the way the body
utilizes vitamin A.17 Further controlled research is needed to determine whether
supplemental vitamin A might prevent birth defects in children born to women on multiple
anticonvulsant therapy. Other research suggests that ingestion of large amounts of vitamin A
may promote the development of birth defects, although the studies are conflicting.
One controlled study revealed that supplementing with 200 mg of vitamin B6 daily for four
weeks resulted in a 45% reduction in phenobarbital blood levels.18 Therefore,
people taking phenobarbital should probably avoid supplementing with large amounts of vitamin
One controlled study revealed that taking anticonvulsant drugs dramatically reduces blood
levels of vitamin B6.19 A nutritional deficiency of vitamin B6 can lead to an
increase in homocysteine blood levels, which
has been associated with atherosclerosis.
Vitamin B6 deficiency is also associated with symptoms such as dizziness, fatigue, mental depression, and seizures. People taking multiple
anticonvulsant drugs should discuss with their doctor whether supplementing with vitamin B6 is
Anemia is an uncommon side effect experienced by people taking anticonvulsant drugs. Though
the cause may be folic acid deficiency in many
cases, a deficiency of vitamin B12 may also be a factor in some instances. Deficiencies of
folic acid and vitamin B12 can lead to nerve and mental problems. One study revealed that
individuals on long-term anticonvulsant therapy, despite having no laboratory signs of anemia,
had dramatically lower levels of vitamin B12 in their cerebrospinal fluid (the fluid that
bathes the brain) when compared with people who were not taking seizure medications.
Improvement in mental status and nerve function was observed in a majority of symptomatic
individuals after taking 30 mcg of vitamin B12 daily for a few days.20 Another
study found that long-term anticonvulsant therapy had no effect on blood levels of vitamin
B12.21 Despite these contradictory findings, people taking anticonvulsant drugs for
several months or years might prevent nerve and mental problems by supplementing with vitamin
Though research results vary, long-term use of anticonvulsant drugs appears to interfere with
vitamin D activity, which might lead to softening of bones (osteomalacia). One study showed that blood levels of
vitamin D in males taking anticonvulsants were lower than those found in men who were not
taking seizure medication.22 In a controlled study, bone strength improved in
children taking anticonvulsant drugs who were supplemented with the activated form of vitamin
D and 500 mg per day of calcium for nine
months.23 Some research suggests that differences in exposure to
sunlight—which normally increases blood levels of vitamin D—might explain why some
studies have failed to find a beneficial effect of vitamin D supplementation. In one
controlled study, blood vitamin D levels in children taking anticonvulsants were dramatically
lower in winter months than in summer months.24 Another study of 450 people in
Florida taking anticonvulsants found that few had drug-induced bone disease.25
Consequently, people taking anticonvulsant drugs who do not receive adequate sunlight should
supplement with 400 IU of vitamin D each day to help prevent osteomalacia.
Two studies showed that individuals taking phenytoin and phenobarbital had lower blood vitamin
E levels than those who received no treatment for seizures.26 27 Though
the consequences of lower blood levels of vitamin E are unknown, people taking multiple
anticonvulsant drugs should probably supplement with 100 to 200 IU of vitamin E daily to
prevent a deficiency.
Some studies have shown that babies born to women taking anticonvulsant drugs have low blood
levels of vitamin K, which might cause bleeding in the infant.28 Though some
researchers recommend vitamin K supplementation prior to delivery,29 30
not all agree that supplementation for women taking anticonvulsant drugs is
necessary.31 Until more information is available, pregnant women or women who might become pregnant
while taking anticonvulsant drugs should discuss vitamin K supplementation with their
1. Mock DM, Mock NI, Nelson RP, Lombard KA. Disturbances in biotin
metabolism in children undergoing long-term anticonvulsant therapy. J Pediatr
Gastroenterol Nutr 1998;26:245–50.
2. Said HM, Redha R, Nylander W. Biotin transport in the human intestine:
inhibition by anticonvulsant drugs. Am J Clin Nutr 1989;49:127–31.
3. Bouillon R, Reynaert J, Claes JH, et al. The effect of anticonvulsant
therapy on serum levels of 25-hydroxy-vitamin D, calcium, and parathyroid hormone. J Clin
Endocrinol Metab 1975;41:1130–5.
4. Friis B, Sardemann H. Neonatal hypocalcaemia after intrauterine
exposure to anticonvulsant drugs. Arch Dis Child 1977;52:239–41.
5. Castro-Gago M, Eiris-Punal J, Novo-Rodriquez 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.
6. Kishi T, Fujita N, Eguchi T, Ueda K. Mechanism for reduction of serum
folate by antiepileptic drugs during prolonged therapy. J Neurol Sci
7. Biale Y, Lewenthal H. Effect of folic acid supplementation on
congenital malformations due to anticonvulsive drugs. Eur J Obstet Gynecol Reprod
8. Nulman I, Laslo D, Koren G. Treatment of epilepsy in pregnancy.
Drugs 1999;57:535–44 [review].
9. Hiilesmaa VK, Teramo K, Granstrom JL, et al. Serum folate
concentrations during pregnancy in women with epilepsy: relation to antiepileptic drug
concentrations, number of seizures, and fetal outcome. Br Med J (Clin Res Ed)
10. Gibberd FB, Nicholls A, Wright MG. The influence of folic acid on the
frequency of epileptic attacks. Eur J Clin Pharmacol 1981;19:57–60.
11. Torres OA, Miller VS, Buist NM, Hyland K. Folinic acid-responsive
neonatal seizures. J Child Neurol 1999;14:529–32.
12. Guidolin L, Vignoli A, Canger R. Worsening in seizure frequency and
severity in relation to folic acid administration. Eur J Neurol
13. Lewis DP, Van Dyke DC, Willhite LA. Phenytoin-folic acid interaction.
Ann Pharmacother 1995;29:726–35 [review].
14. Berg MJ, Rivey MP, Vern BA, et al. Phenytoin and folic acid:
individualized drug-drug interaction. Ther Drug Monit 1983;5:395–9.
15. Reynolds EH. Effects of folic acid on the mental state and fit
frequency of drug treated epileptic patients. Lancet 1967;1:1086.
16. Eros E, Geher P, Gomor B, Czeizel AE. Epileptogenic activity of folic
acid after drug induces SLE (folic acid and epilepsy). Eur J Obstet Gynecol Reprod
17. Nau H, Tzimas G, Mondry M, et al. Antiepileptic drugs alter
endogenous retinoid concentrations: a possible mechanism of teratogensis of anticonvulsant
therapy. Life Sci 1995;57:53–60.
18. Walter-Sack I, Klotz U. Influence of diet and nutrition status on
drug metabolism. Clin Pharmacokinet 1996;31:47–64.
19. Schwaninger M, Ringleb P, Winter R, et al. Elevated plasma
concentrations of homocysteine in antiepileptic drug treatment. Epilepsia
20. Frenkel EP, McCall MS, Sheehan RG. Cerebrospinal fluid folate, and
vitamin B12 in anticonvulsant-induced megaloblastosis. J Lab Clin Med
21. Schwaninger M, Ringleb P, Winter R, et al. Elevated plasma
concentrations of homocysteine in antiepileptic drug treatment. Epilepsia
22. Telci A, Cakatay U, Kurt BB, et al. Changes in bone turnover and
deoxypyridinoline levels in epileptic patients Clin Chem Lab Med 2000
23. Jekovec-Vrhovsek M, Kocijancic A, Prezelj J. Effect of vitamin D and
calcium on bone mineral density in children with CP and epilepsy in full-time care. Dev
Med Child Neurol 2000;42:403–5.
24. Riancho JA, Del Arco C, Arteaga R, et al. Influence of solar
irradiation on vitamin D levels in children on anticonvulsant drugs. Acta Neurol
25. Williams C, Netzloff M, Folkerts L, et al. Vitamin D metabolism and
anticonvulsant therapy: effect of sunshine on incidence of osteomalacia. South Med J
26. Higashi A, Tamari H, Ikeda T, et al. Serum vitamin E concentration in
patients with severe multiple handicaps treated with anticonvulsants. Pediatr Pharmacol
(New York) 1980;1:129–34.
27. Higashi A, Ikeda T, Matsukura M, Matsuda I. Serum zinc and vitamin E
concentrations in handicapped children treated with anticonvulsants. Dev Pharmacol
28. 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.
29. Nulman I, Laslo D, Koren G. Treatment of epilepsy in pregnancy.
Drugs 1999;57:535–44 [review].
30. 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.
31. Hey E. Effect of maternal anticonvulsant treatment on neonatal blood
coagulation. Arch Dis Child Fetal Neonatal Ed 1999;81:F208–10.
32. Olin BR, et. Central Nervous System Drugs, Sedatives and Hypnotics,
Barbiturates. In: Drug Facts and Comparisons, St. Louis, MO: Facts and Comparisons,