Ginkgo
Effect: Possible Harmful Interaction
The herb ginkgo (Ginkgo biloba) has been used to treat
Alzheimer’s
disease and ordinary age-related memory loss, among many
other conditions. This interaction involves potential contaminants in ginkgo, not
ginkgo itself.
A recent study found that a natural nerve toxin present in the seeds of Ginkgo biloba made its way into standardized ginkgo extracts prepared from the leaves. This toxin has been associated with convulsions and death in laboratory animals.
The detected amounts of this toxic substance are considered harmless. However, given the lack of satisfactory standardization of herbal formulations in the United States, it is possible that some batches of product might contain greater amounts of the toxin depending on the season of harvest. In light of these findings, taking a ginkgo product that happened to contain significant levels of the nerve toxin might theoretically prevent an anticonvulsant from working as well as expected.
Glutamine
Effect: Possible Harmful Interaction
The amino acid glutamine is converted to glutamate in the body. Glutamate
is thought to act as a neurotransmitter (chemical that enables
nerve transmission). Because anticonvulsants work (at least in part) by blocking
glutamate pathways in the brain, high dosages of the amino acid glutamine might
theoretically diminish an anticonvulsant’s effect and increase the risk of
seizures.
Grapefruit Juice
Effect: Possible Harmful Interaction
Grapefruit juice slows the body’s normal breakdown of several drugs, including
the anticonvulsant carbamazepine, allowing it to build up to potentially dangerous
levels in the blood. A recent study indicates this effect can last for three days
or more following the last glass of juice. Because of this risk, if one uses
carbamazepine, the safest approach is to avoid grapefruit juice altogether.
Ipriflavone
Effect: Possible Harmful Interaction
Ipriflavone, a synthetic isoflavone that slows bone breakdown,
is used to treat osteoporosis. Test-tube studies indicate that ipriflavone
might increase blood levels of the anticonvulsants carbamazepine and
phenytoin when they are taken therapeutically. Ipriflavone
was found to inhibit a liver enzyme involved in the body’s normal breakdown of
these drugs, thus allowing them to build up in the blood. Higher drug levels
increase the risk of adverse effects.
Because anticonvulsants are known to contribute to the development of osteoporosis, a concern is that the use of ipriflavone for this drug-induced osteoporosis could result in higher blood levels of the drugs with potentially serious consequences. Persons taking either of these drugs should use ipriflavone only under medical supervision.
Hops, Kava, Passionflower, Valerian
Effect: Possible Harmful Interaction
The herb kava (Piper methysticum) has a sedative effect and is
used for anxiety and insomnia. Combining kava with
anticonvulsants, which possess similar depressant effects, could result in
“add-on” or excessive physical depression, sedation, and impairment. In one case
report, a fifty-four-year-old man was hospitalized for lethargy and
disorientation, side effects attributed to his having taken the combination of
kava and the anti-anxiety agent alprazolam (Xanax) for three days.
Other herbs having a sedative effect that might cause problems when combined with anticonvulsants include ashwagandha (Withania somnifera), calendula (Calendula officinalis), catnip (Nepeta cataria), hops (Humulus lupulus), lady’s slipper (Cypripedium species), lemon balm (Melissa officinalis), passionflower (Passiflora incarnata), sassafras (Sassafras officinale), skullcap (Scutellaria lateriflora), valerian (Valeriana officinalis), and yerba mansa (Anemopsis californica). Because of the potentially serious consequences, one should avoid combining these herbs with anticonvulsants or other drugs that also have sedative or depressant effects, unless advised by a physician.
Nicotinamide
Effect: Possible Harmful Interaction
Nicotinamide (also called niacinamide) is a compound produced by the body’s
breakdown of niacin (vitamin B3). It is a supplemental form
that does not possess the flushing side effect or the cholesterol-lowering ability
of niacin. Nicotinamide appears to increase blood levels of carbamazepine and
primidone, possibly requiring a reduction in drug dosage to
prevent toxic effects.
Carbamazepine blood levels increased in two children with epilepsy
after they were given nicotinamide, but the fact that the children were on several
anticonvulsant drugs clouds the issue somewhat. Similarly, nicotinamide given to
three children on primidone therapy increased blood levels of primidone. It is
thought that nicotinamide may interfere with the body’s normal breakdown of these
anticonvulsant agents, allowing them to build up in the blood.
Dong Quai, St. John’s Wort
Effect: Possible Harmful Interaction
St. John’s wort (Hypericum perforatum) is primarily used to
treat mild to moderate depression. The herb dong quai
(Angelica sinensis) is often recommended for menstrual
disorders such as dysmenorrhea, premenstrual syndrome (PMS), and
irregular menstruation.
The anticonvulsant agents carbamazepine, phenobarbital, and valproic acid have been reported to cause increased sensitivity to the sun, amplifying the risk of sunburn or skin rash. Because St. John’s wort and dong quai may also cause this problem, taking them during treatment with these drugs might add to this risk.
It may be a good idea to use sunscreen or wear protective clothing during sun exposure if one takes one of these herbs while using these anticonvulsants.
Biotin
Effect: Supplementation Possibly Helpful, but Take at a Different Time of Day
Anticonvulsants may deplete biotin, an essential water-soluble B
vitamin, possibly by competing with it for absorption in the intestine. It is not
clear, however, whether this effect is great enough to be harmful.
Blood levels of biotin were found to be substantially lower in 404 people with
epilepsy on long-term treatment with anticonvulsants compared with 112 untreated
people with epilepsy. The effect occurred with phenytoin, carbamazepine,
phenobarbital, and primidone. Valproic acid appears to affect biotin
to a lesser extent than other anticonvulsants. A test-tube study suggested that
anticonvulsants might lower biotin levels by interfering with the way biotin is
transported in the intestine.
Biotin supplementation may be beneficial if one is on long-term anticonvulsant therapy. To avoid a potential interaction, one should take the supplement two to three hours apart from the drug. It has been suggested that the action of anticonvulsant drugs may be at least partly related to their effect of reducing biotin levels. For this reason, it may be desirable to take enough biotin to prevent a deficiency, but not an excessive amount.
Folate
Effect: Supplementation Possibly Helpful
Folate (also known as folic acid) is a B vitamin that plays
an important role in many vital aspects of health. Carbamazepine appears to lower
blood levels of folate by speeding up its normal breakdown by the body and also by
decreasing its absorption. Other antiseizure drugs can also reduce levels of
folate in the body.
Low folate can lead to anemia and reduced white blood cell
count, and folate supplements have been shown to help prevent these complications
of carbamazepine treatment.
Adequate folate intake is also necessary to prevent neural tube birth defects,
such as spina
bifida and anencephaly. Because anticonvulsant drugs deplete
folate, babies born to women taking anticonvulsants are at increased risk for such
birth defects. Anticonvulsants may also play a more direct role in the development
of birth defects.
The low serum folate caused by anticonvulsants can raise homocysteine levels, a condition hypothesized to increase the risk of heart disease. However, the case for taking extra folate during anticonvulsant therapy is not as simple as it might seem. It is possible that folate supplementation itself might impair the effectiveness of anticonvulsant drugs, and physician supervision is necessary.
Calcium
Effect: Supplementation Probably Helpful, but Take at a Different Time of Day
Anticonvulsant drugs may impair calcium absorption and, in this way, increase the risk of osteoporosis and other bone disorders. Calcium absorption was compared in twelve people on anticonvulsant therapy (all taking phenytoin and some also taking carbamazepine, phenobarbital, and/or primidone) and twelve people who received no treatment. Calcium absorption was found to be 27 percent lower in the treated participants.
An observational study found low calcium blood levels in 48 percent of 109 people taking anticonvulsants. Other findings in this study suggested that anticonvulsants might also reduce calcium levels by directly interfering with parathyroid hormone, a substance that helps keep calcium levels in proper balance. A low blood level of calcium can itself trigger seizures, and this might reduce the effectiveness of anticonvulsants.
Calcium supplementation may be beneficial for people taking anticonvulsant drugs. However, some studies indicate that antacids containing calcium carbonate may interfere with the absorption of phenytoin and perhaps other anticonvulsants. For this reason, one should take calcium supplements and anticonvulsant drugs several hours apart if possible.
Carnitine
Effect: Supplementation Possibly Helpful
Carnitine is an amino acid that has been used for heart conditions, Alzheimer’s
disease, and intermittent claudication. Intermittent claudication is a possible
complication of atherosclerosis, in which impaired blood circulation causes
severe pain in calf muscles during walking or exercising.
Long-term therapy with anticonvulsant agents, particularly valproic acid, is associated with low levels of carnitine. However, it is not clear whether the anticonvulsants cause the carnitine deficiency or whether it occurs for other reasons. It has been hypothesized that low carnitine levels may contribute to valproic acid’s damaging effects on the liver. The risk of this liver damage increases in children younger than twenty-four months, and carnitine supplementation may be protective. However, in one double-blind crossover study, carnitine supplementation produced no real improvement in well-being as assessed by parents of children receiving either valproic acid or carbamazepine.
L-carnitine supplementation may be advisable in certain cases, such as in infants and young children (especially those younger than two years) who have neurologic disorders and are receiving valproic acid and multiple anticonvulsants.
Vitamin D
Effect: Supplementation Possibly Helpful
Anticonvulsant drugs may interfere with the activity of vitamin D. As
proper handling of calcium by the body depends on vitamin D, this may be another
way that these drugs increase the risk of osteoporosis and related bone
disorders.
Anticonvulsants appear to speed up the body’s normal breakdown of vitamin D, decreasing the amount of the vitamin in the blood. A survey of forty-eight people taking both phenytoin and phenobarbital found significantly lower levels of calcium and vitamin D in many of them compared with thirty-eight untreated persons. Similar but lesser changes were seen in thirteen people taking phenytoin or phenobarbital alone. This effect may be apparent only after several weeks of treatment.
Another study found decreased blood levels of one form of vitamin D but normal levels of another. Because there are multiple forms of vitamin D circulating in the blood, the body might be able to adjust in some cases to keep vitamin D in balance, at least for a time, despite the influence of anticonvulsants.
Adequate sunlight exposure may help overcome the effects of anticonvulsants on vitamin D by stimulating the skin to manufacture the vitamin. Of 450 people on anticonvulsants residing in a Florida facility, none was found to have low blood levels of vitamin D or evidence of bone disease. This suggests that environments providing regular sun exposure may be protective. Persons regularly taking anticonvulsants, especially those taking combination therapy and those with limited exposure to sunlight, may benefit from vitamin D supplementation.
Vitamin K
Effect: Supplementation Possibly Helpful for Pregnant Women
Phenytoin, carbamazepine, phenobarbital, and primidone speed up the normal
breakdown of vitamin K into inactive byproducts, thus depriving the body
of active vitamin K. This can lead to bone problems, such as osteoporosis. In
addition, use of these anticonvulsants can lead to a vitamin K deficiency in
babies born to mothers taking the drugs, resulting in bleeding disorders or facial
bone abnormalities in the newborns. Mothers who take these anticonvulsants may
need vitamin K supplementation during pregnancy to prevent these conditions in
their newborns.
Bibliography
Asadi-Pooya, A. A., and E. Ghetmiri. “Folic Acid Supplementation Reduces the Development Abnormalities in Children Receiving Carbamazepine.” Epilepsy and Behavior 8 (2006): 228-231.
De Vivo, D. C., et al. “L-carnitine Supplementation in Childhood Epilepsy.” Epilepsia 39 (1998): 1216-1225.
Kishi, T., et al. “Mechanism for Reduction of Serum Folate by Antiepileptic Drugs During Prolonged Therapy.” Journal of the Neurological Sciences 145 (1997): 109-112.
Lewis, D. P., et al. “Drug and Environmental Factors Associated with Adverse Pregnancy Outcomes: Part 1–Antiepileptic Drugs, Contraceptives, Smoking, and Folate.” Annals of Pharmacotherapy 32 (1998): 802-817.
Ono, H., et al. “Plasma Total Homocysteine Concentrations in Epileptic Patients Taking Anticonvulsants.” Metabolism 46 (1997): 959-962.
Takanaga, H., et al. “Relationship Between Time After Intake of Grapefruit Juice and the Effect on Pharmacokinetics and Pharmacodynamics of Nisoldipine in Healthy Subjects.” Clinical Pharmacology and Therapeutics 67 (2000): 201-214.
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