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 deficiency.

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.

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.⁵ 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.

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.⁶ Another study found that long-term anticonvulsant therapy had no effect on blood levels of vitamin B12.⁷ Despite these contradictory findings, people taking anticonvulsant drugs for several months or years might prevent nerve and mental problems by supplementing with vitamin B12.

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.⁸ Therefore, people taking phenobarbital should probably avoid supplementing with large amounts of vitamin B6.

One controlled study revealed that taking anticonvulsant drugs dramatically reduces blood levels of vitamin B6.⁹ 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 advisable.

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.¹⁰ Another study found that long-term anticonvulsant therapy had no effect on blood levels of vitamin B12.¹¹ Despite these contradictory findings, people taking anticonvulsant drugs for several months or years might prevent nerve and mental problems by supplementing with vitamin B12.

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.¹² Therefore, people taking phenobarbital should probably avoid supplementing with large amounts of vitamin B6.

One controlled study revealed that taking anticonvulsant drugs dramatically reduces blood levels of vitamin B6.¹³ 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 advisable.

Long-term treatment with phenobarbital results in dramatic reductions in folic acid blood levels, though the clinical significance of this effect is unclear.¹⁴ Nevertheless, some healthcare practitioners might recommend supplemental folic acid to individuals taking phenobarbital.

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.¹⁵ 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.¹⁶ Other practitioners suggest that 1 mg or less of folic acid each day is sufficient to prevent deficiency during pregnancy.¹⁷

One well-controlled study showed that adding folic acid to multiple anticonvulsant therapy resulted in reduced seizure frequency.¹⁸ In addition, three infants with seizures who were unresponsive to medication experienced immediate relief following supplementation with the active form of folic acid.¹⁹

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.^{20 , 21 , 22 , 23} 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.²⁴ 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.

One controlled study showed that taking phenobarbital resulted in reduced blood levels of L-carnitine.²⁵ 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.

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.²⁶ 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.²⁷ 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.²⁸ Another study of 450 people in Florida taking anticonvulsants found that few had drug-induced bone disease.²⁹ 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.

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.³⁰ Though some researchers recommend vitamin K supplementation prior to delivery,^{31 , 32} not all agree that supplementation for women taking anticonvulsant drugs is necessary.³³ Until more information is available, pregnant women or women who might become pregnant while taking anticonvulsant drugs should discuss vitamin K supplementation with their healthcare practitioner.