Carbamazepine is an anticonvulsant agent used primarily to prevent seizures in conditions such as epilepsy.
Other anticonvulsant agents include
valproic acid. In some cases, combination therapy with two or more anticonvulsant drugs may be used.
The herb ginkgo
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.1 This toxin has been associated with convulsions and death in laboratory animals.2,3,4
Fortunately, the detected amounts of this toxic substance are considered harmless.5
However, given the lack of satisfactory standardization of herbal formulations in the US, it is possible that some batches of product might contain higher contents 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.
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 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.6 A recent study indicates this effect can last for 3 days or more following the last glass of juice.7
Because of this risk, if you use carbamazepine, the safest approach is to avoid grapefruit juice altogether.
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.8
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.
Individuals taking either of these drugs should use ipriflavone only under medical supervision.
The herb kava
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 54-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 3 days.9
Other herbs having a sedative effect that might cause problems when combined with anticonvulsants include
lemon balm(Melissa officinalis),
passionflower(Passiflora incarnata), sassafras (Sassafras officinale),
valerian(Valeriana officinalis), and yerba mansa (Anemopsis californica).
Because of the potentially serious consequences, you should avoid combining these herbs with anticonvulsants or other drugs that also have sedative or depressant effects unless advised by your physician.
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,10 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.11
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.
St. John's wort
is primarily used to treat mild to moderate depression.
The herb dong quai
is often recommended for menstrual disorders such as dysmenorrhea, 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 wear a sunscreen or protective clothing during sun exposure if you take one of these herbs while using these anticonvulsants.
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 to 112 untreated people with epilepsy.12
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.13
Biotin supplementation may be beneficial if you are on long-term anticonvulsant therapy. To avoid a potential interaction, take the supplement 2 to 3 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 (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.14 Other antiseizure drugs can also reduce levels of folate in the body.15-19
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.41
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.21
The low serum folate caused by anticonvulsants can raise
homocysteine levels, a condition hypothesized to increase the risk of heart disease.20
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.
Anticonvulsant drugs may impair calcium absorption and, in this way, increase the risk of osteoporosis and other bone disorders.
Calcium absorption was compared in 12 people on anticonvulsant therapy (all taking phenytoin and some also taking carbamazepine, phenobarbital, and/or primidone) and 12 people who received no treatment.22
Calcium absorption was found to be 27% lower in the treated participants.
An observational study found low calcium blood levels in 48% of 109 people taking anticonvulsants.24
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.25,26
For this reason, take calcium supplements and anticonvulsant drugs several hours apart if possible.
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.27,28 However, it isn't 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.27,28,30 The risk of this liver damage increases in children younger than 24 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.32
L-carnitine supplementation may be advisable in certain cases, such as in infants and young children (especially those younger than 2 years) who have neurologic disorders and are receiving valproic acid and multiple anticonvulsants.31
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. (See the previous Calcium topic.)
Anticonvulsants appear to speed up the body's normal breakdown of vitamin D, decreasing the amount of the vitamin in the blood.35 A survey of 48 people taking both phenytoin and phenobarbital found significantly lower levels of calcium and vitamin D in many of them as compared to 38 untreated individuals.36
Similar but lesser changes were seen in 13 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.37 Because there are multiple forms of vitamin D circulating in the blood,38
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.38
Of 450 people on anticonvulsants residing in a Florida facility, none were 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.
Individuals regularly taking anticonvulsants, especially those taking combination therapy and those with limited exposure to sunlight, may benefit from vitamin D supplementation.
Phenytoin, carbamazepine, phenobarbital, and primidone speed up the normal breakdown of vitamin K into inactive by-products, thus depriving the body of active vitamin K. This can lead to bone problems, such as osteoporosis. Also, 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.39,40
Mothers who take these anticonvulsants may need vitamin K supplementation during pregnancy to prevent these conditions in their newborns.
Arenz A, Klein M, Fiehe K. Occurrence of neurotoxic 4'-O-methylpyridoxine in
leaves, ginkgo medications and Japanese ginkgo food.
Mizuno N, Kawakami K, Morita E. Competitive inhibition between 4'-substituted pyridoxine analogues and pyridoxal for pyridoxal kinase from mouse brain.
J Nutr Sci Vitaminol (Tokyo).
Wada K, Ishigaki S, Ueda K, et al. An antivitamin B6, 4'-methoxypyridoxine, from the seed of
Chem Pharm Bull (Tokyo).
Yagi M, Wada K, Sakata M, et al. Studies on the constituents of edible and medicinal plants. IV. Determination of 4-O-methylpyridoxine in serum of the patient with gin-nan food poisoning [in Japanese; English abstract].
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Takanaga H, Ohnishi A, Murakami H, et al. Relationship between time after intake of grapefruit juice and the effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects.
Clin Pharmacol Ther.
Monostory K, Vereczkey L, Levai F, et al. Ipriflavone as an inhibitor of human cytochrome P450 enzymes.
Br J Pharmacol.
Almeida JC, Grimsley EW. Coma from the health food store: interaction between kava and alprazolam.
Ann Intern Med.
Bourgeois BF, Dodson WE, Ferrendelli JA. Interactions between primidone, carbamazepine, and nicotinamide.
Krause KH, Bonjour JP, Berlit P, et al. Biotin status of epileptics.
Ann N Y Acad Sci.
Said HM, Redha R, Nylander W. Biotin transport in the human intestine: inhibition by anticonvulsant drugs.
Am J Clin Nutr.
Kishi T, Fujita N, Eguchi T, et al. Mechanism for reduction of serum folate by antiepileptic drugs during prolonged therapy.
J Neurol Sci.
Reynolds EH. Mental effects of anticonvulsants, and folic acid metabolism.
Berg MJ, Stumbo PJ, Chenard CA, et al. Folic acid improves phenytoin pharmacokinetics.
J Am Diet Assoc.
Lewis DP, Van Dyke DC, Willhite LA, et al. Phenytoin-folic acid interaction.
Lewis DP, Van Dyke DC, Stumbo PJ, et al. Drug and environmental factors associated with adverse pregnancy outcomes. Part I: Antiepileptic drugs, contraceptives, smoking, and folate.
Ono H, Sakamoto A, Eguchi T, et al. Plasma total homocysteine concentrations in epileptic patients taking anticonvulsants.
Wahl TO, Gobuty AH, Lukert BP. Long-term anticonvulsant therapy and intestinal calcium absorption.
Clin Pharmacol Ther.
Weinstein RS, Bryce GF, Sappington LJ, et al. Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment.
J Clin Endocrinol Metab.
Carter BL, Garnett WR, Pellock JM, et al. Effect of antacids on phenytoin bioavailability.
Ther Drug Monit.
McElnay JC, Uprichard G, Collier PS. The effect of activated dimethicone and a proprietary antacid preparation containing this agent on the absorption of phenytoin.
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De Vivo DC, Bohan TP, Coulter DL, et al. L-carnitine supplementation in childhood epilepsy: current perspectives.
Coulter DL. Carnitine deficiency: a possible mechanism for valproate hepatotoxicity [letter].
Ater SB, et al. A developmental center population treated with VPA and L-carnitine. In: Update: inborn errors of metabolism in the patient with epilepsy. Sigma-Tau Pharmaceuticals; 1993.
Dreifuss FE, Langer DH. Hepatic considerations in the use of antiepileptic drugs.
Freeman JM, Vining EP, Cost S, et al. Does carnitine administration improve the symptoms attributed to anticonvulsant medications? A double-blinded, crossover study.
Hahn TJ, Hendin BA, Scharp CR, et al. Effect of chronic anticonvulsant therapy on serum 25-hydroxycalciferol levels in adults.
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Jubiz W, Haussler MR, McCain TA, et al. Plasma 1,25-dihydroxyvitamin D levels in patients receiving anticonvulsant drugs.
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Brodie MJ, Boobis AR, Dollery CT, et al. Rifampicin and vitamin D metabolism.
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Williams C, Netzloff M, Folkerts L, et al. Vitamin D metabolism and anticonvulsant therapy: effect of sunshine on incidence of osteomalacia.
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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.
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.
Asadi-Pooya AA, Ghetmiri E. Folic acid supplementation reduces the development abnormalities in children receiving carbamazepine.
Epilepsy Behav. 2005 Dec 24. [Epub ahead of print]
Last reviewed December 2015 by EBSCO CAM Review Board
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