Several studies have shown that multiple anticonvulsant therapy reduces blood levels of folic acid and dramatically increases homocysteine levels. Homocysteine, a potential marker for folic acid deficiency, is a compound used experimentally to induce seizures and is associated with atherosclerosis.

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

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

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. 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. 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.

Valproic acid causes depletion of carnitine in children, and blood carnitine levels are often low in people taking valproic acid for long periods of time. While there have been several case reports of valproic acid-related carnitine deficiency causing abdominal pain in children, there is controversy about the need for carnitine supplements in children taking valproic acid.

Complete disappearance of severe valproic acid-induced abdominal pain was achieved in one child with intractable epilepsy immediately following the introduction of 300 mg per day of L-carnitine. Carnitine supplementation (50 mg per 2.2 pounds of body weight) has protected children from valproic acid-induced increases in blood ammonia levels in some research, though other published work has questioned whether the depletion of carnitine and the increase in blood ammonia levels (both caused by valproic acid) are actually related to each other. This last report found that the depletion of carnitine was significantly more severe when epileptics were taking valproic acid together with other anti-seizure medications. A double-blind, crossover study found that carnitine supplementation (100 mg per 2.2 pounds of body weight) was no more effective than placebo in improving the sense of well-being in children treated with valproic acid. To date, the question of whether carnitine supplementation is beneficial for people taking valproic acid remains unresolved. However, a panel of pediatric neurologists and experts on L-carnitine supplementation strongly recommended oral L-carnitine supplementation for all infants and children taking valproic acid, as well as for adults with carnitine deficiency syndromes, people with valproic acid-induced liver and kidney toxicity, people on kidney dialysis, and premature infants on total parenteral nutrition (intravenous feeding). The panel recommended an amount of 100 mg per 2.2 pounds of body weight per day, up to a maximum of 2 grams per day.

On the basis of the biochemical actions of valproic acid, it has been suggested that people taking valproic acid should make sure they have adequate intakes of vitamin E and selenium. The importance of supplementation with either nutrient has not yet been tested, however.

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. 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. 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. Another study of 450 people in Florida taking anticonvulsants found that few had drug-induced bone disease. 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. Though some researchers recommend vitamin K supplementation prior to delivery, not all agree that supplementation for women taking anticonvulsant drugs is necessary. 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.