Epilepsy & Behavior 2, 524-532 (2001)
doi:10.1006/ebeh.2000.0050, available online at http://www.idealibrary.com on IDEAL


Herbal Medicines and Epilepsy: The Potential for Benefit and Adverse Effects

Marcello Spinella, Ph.D.

Social and Behavioral Sciences, Richard Stockton College of New Jersey, P.O. Box 195, Pomona, New Jersey 08240

Received May 24, 2001; revised September 13, 2001; accepted for publication September 25, 2001

The widespread availability and use of herbal medicines raise the potential for adverse effects in the epilepsy population. Herbal sedatives (kava, valerian, chamomile, passionflower) may potentiate the effects of antiepileptic medications, increasing their sedative and cognitive effects. Despite some antiseizure effects in animal models, they should not be used in place of standard seizure medications because efficacy has not been established. Anecdotal, uncontrolled observations suggest that herbal stimulants containing ephedrine (ephedra or ma huang) and caffeine (cocoa, coffee, tea, mate´ , guarana, cola or kola) can exacerbate seizures in people with epilepsy, especially when taken in combination. Ginkgo and ginseng may also exacerbate seizures although the evidence for this is similarly anecdotal and uncertain. St. John’s wort has the potential to alter medication pharmacokinetics and the seizure threshold. The essential oils of many plants contain epileptogenic compounds. There is mixed evidence for evening primrose and borage lowering the seizure threshold. Education of both health care providers and patients is the best way to avoid unintentional and unnecessary adverse reactions to herbal medicines. © 2001 Elsevier Science

There is widespread and increasing interest in complementary and alternative medicines (CAMs), including herbal medicines (1). National surveys suggest that 42% of Americans surveyed have recently used at least one such form of therapy. People also tend to use CAM for chronic conditions that do not respond well to conventional treatments (e.g., back problems, anxiety, depression, and headaches). Further, a large proportion of CAM consumers (40%) do not disclose their use of CAMs to their physicians, and it was estimated that 15 million American adults took prescription medications concurrently with herbal medications and/or high-dose vitamins in 1997. People with epilepsy are no exception in this regard: 24% of patients in one tertiary care epilepsy clinic reported using CAMs (2). Users of CAMs were found with all levels of education, ranging from incomplete high

1 To whom correspondence should be addressed. E-mail: Marcello.Spinella@stockton.edu.

school education to the postgraduate level. CAM users did not significantly differ from nonusers in terms of age, gender, or race. Of the CAM users, 41% used herbal medicines and supplements. Similar to the findings of Eisenberg and colleagues (1), Peebles and colleagues (2) found that a minority (31%) of CAM users informed their physicians.

This proportion may vary across ethnic and cultural groups. A sample in Nigeria found 52% of epilepsy patients using some form of CAM (3). Further, herbs/supplements are among the most commonly used forms of CAM, and only 31% of epilepsy patients in one study informed their neurologists about their CAM use (2). This creates an enormous potential for unintentional side effects and interactions with prescription medications. Clearly it is in the best interests of health care professionals to know and understand the CAM therapies used by their patients to advise them accordingly about their safety and efficacy (4).


1525-5050/01 $35.00
Copyright © 2001 Elsevier Science
All rights reserved.

Herbal Medicines and Epilepsy 525

Sedative Herbs

Common name Botanical name Main active constituent

Chamomile Matricaria recutita
Chamaemelum nobile
Piper methysticum
Passiflora coerulea
Passiflora edulis
Valerian Valeriana officinalis Sesquiterpenes

Note. See text for references.

Herbal medicine is an area of CAM that is readily amenable to empirical research. Although a fair amount of research is available for certain herbal medicines, much more is needed and many basic safety and efficacy issues remain to be addressed. However, active chemical constituents and mechanisms of action have been identified in several herbal medicines that are commonly sold as supplements. Numerous herbal medicines have effects in the central nervous system and on hepatic metabolism and thus have at least the theoretical potential for affecting seizures in patients with epilepsy and interacting with some antiepileptic medications. These include herbal sedatives (kava, valerian, chamomile, passionflower), stimulants (ephedra, cocoa, coffee, tea, mate´, guarana, cola), cognitive enhancers (ginkgo and ginseng), and several essential oils.

This article reviews the known physiological actions of several herbal medicines and their documented effects on seizures, and suggests guidelines for physicians to use when counseling their patients with epilepsy about these products.



Kava (Piper methysticum) is a plant native to the South Pacific islands, and has a historical reputation for creating relaxation (5). There is preliminary evidence that kava is effective in treating anxiety (6). The active constituents in kava appear to be the kavalactones (Table 1), including kavain, dihydrokavain, yangonin, dimethoxyyangonin, methysticin, and dihydromethysticin (5). A few mechanisms of kava have been determined, but two appear the most relevant to seizure disorders: facilitation of GABA transmission and inhibition of voltage-gated ion channels. Kavalac-

tones facilitate GABA transmission, enhancing ligand binding to the GABAA receptor through a nonbenzodiazepine receptor site (7–9). Kavalactones also inhibit voltage-gated Na+ and Ca2+ channels at concentrations consistent with those reached in the brain by peripheral administration (10–13). It has been proposed that they bind to the Na+ channel in its inactivated state and prolong inactivation (12). Micromolar concentrations of kavain inhibit L-type Ca2+ channels, significantly reducing the subsequent release of endogenous glutamate (14).

Electrophysiological studies have shown that kavain increases slow-wave activity in both animals and humans (15, 16). Kava extract alone has minimal effects on cognitive performance in commonly used oral doses (17). However, combination with other CNS depressants such as ethanol and barbiturates produces synergistic effects (8, 17). Kavalactones have been investigated for their antiseizure effects only in animals (18 –20). However, they only have a weak effect on strychnine-induced seizures (19). Kavain reduces excitatory activity in hippocampal slices, but does not appear to affect long-term potentiation or synaptic plasticity (21).

Although kava has some antiseizure effects in animal models, it has not been tested for efficacy in humans. A limited amount of kava tolerance develops with chronic treatment in mice (22). It is uncertain to what degree tolerance occurs in humans and whether a rebound hyperexcitability can occur on sudden discontinuation.


Valerian (Valeriana officinalis) is a flowering herb native to Europe and Asia, but now grown in most parts of the world. The use of valerian extends back at least 1000 years, and it gained a reputation in 16thcentury Europe as a treatment for epilepsy (23). Current popular interest in valerian is primarily for its effects on sleep. Preliminary research suggests that valerian may improve sleep quality (24–26).

Valerian’s active chemical constituents are classified as monoterpenes and sesquiterpenes (27). Although GABA is present in valerian extracts, its brain bioavailability via oral administration is uncertain (28). However, other GABAergic mechanisms may be at work: valerian constituents inhibit enzymatic breakdown of GABA and enhance benzodiazepine binding (29, 30). Valerian has sedative effects in animals that are potentiated by barbiturates, and it reduces the anxiogenic effects of diazepam withdrawal (31–33).

Copyright © 2001 Elsevier Science
All rights reserved.

526 Marcello Spinella

Weak antiseizure effects have been shown in mice (31, 33).

In humans, valerian produces a mild decrease in attention and processing of complex information (26). There is little or no current proof that valerian has antiseizure effects. The historical reputation of valerian as a treatment for epilepsy should be considered in light of the lack of other contemporaneous treatments for epilepsy (23).


A few members of the passionflower family, such as Passiflora coerulea and Passiflora edulis, are known for their sedative effects. Native Americans employed a passionflower tea for its sedative and anxiolytic effects. The active constituent is believed to be the flavonoid chrysin (5,7-dihydroxyflavone), which acts as a partial agonist at benzodiazepine receptors with micromolar affinity (34, 35). Animal studies have demonstrated sedative and anxiolytic effects of chrysin (35, 36). However, it has not yet been empirically tested in humans. One study showed antiseizure effects of chrysin on pentylenetetrazol-induced seizures in mice, which were prevented by preinjection of a benzodiazepine antagonist (37).


German and Roman chamomile (Matricaria recutita and Chamaemelum nobile, respectively) are perennial flowering herbs that grow in widespread regions, including Europe, Africa, and Asia. It has been known traditionally for its mild relaxing effects. A candidate constituent for this effect is apigenin, a flavonoid chemical that binds specifically with micromolar affinity to the benzodiazepine receptor (38). However, the sedative effects are not blocked by a specific benzodiazepine antagonist (Ro 15-1788), so its mechanism is still uncertain (39). Apigenin does have anxiolytic and sedative effects in some animal models, but no antiseizure effects. Although it is listed as Generally Regarded as Safe (GRAS) by the Food and Drug Administration, evidence for its effectiveness in humans has yet to be demonstrated empirically.


There are several herbal supplements with known stimulant effects that may exacerbate seizure disor-

Stimulant Herbs

Common name Botanical name Main active constituent

Ephedra species
Theobroma cacao
Caffeine, Theophylline,
Coffee Coffea arabica Caffeine, Theophylline,
  Coffea robusta  
Cola, kola Cola acuminata Caffeine, Theophylline,
  Cola nitida  
Guarana Paulinia cupana Caffeine, Theophylline, Theobromine
Mate´ Ilex paraguariensis Caffeine, Theophylline,
Tea Camellia sinensis Caffeine, Theophylline,

Note. See text for references.

ders. The most common herbal stimulants contain the drugs ephedrine and caffeine (Table 2).


The stimulant drug ephedrine is present in many species of ephedra (e.g., Ephedra sinica), which are often referred to by the Chinese name ma huang. Ephedra has been used traditionally as a stimulant and a treatment for asthma. Ephedra sinica contains approximately 1.25% ephedrine, as well as several other related alkaloids such as pseudoephedrine, methylephedrine, and norpseudoephedrine (40). The stimulant and sympathomimetic effects of ephedrine are mediated by its agonist effects at a1, b1, and b2 receptors (41).

An analysis of adverse events reported by physicians to the FDA between June 1, 1997, and March 31, 1999 (42), revealed several cases of seizures temporally associated with ephedra ingestion. No apparent prior history of seizures was reported for these cases, but the ephedra was taken in combination with other stimulants (e.g., caffeine or phenylpropanolamine hydrochloride). This is a small number of seizures relative to the large numbers of people who consume ephedra in the general population. It is also small relative to the overall number of reported adverse events (7/140), but it underscores the potential danger to those at risk for seizures. Other monoamine stimulants, amphetamine and cocaine, can similarly exacerbate seizure disorders (43, 44).

Copyright © 2001 Elsevier Science
All rights reserved.

Herbal Medicines and Epilepsy 527

Caffeine-Containing Stimulants

Caffeine is one of the most consumed stimulants in the world. Along with its methylxanthine relatives, theophylline and theobromine, it is present in eight species of plants that are commonly available as food and supplements. These include coffee (Coffea arabica and Coffea robusta), tea (Camellia sinensis), cocoa (Theobroma cacao), cola or kola (Cola acuminata and Cola nitida), maté (Ilex paraguariensis), and guarana (Paulinia cupana). Coffee, tea, and cocoa are arguably the most popular in Western countries, but other caffeine-containing herbs are still readily available, often in supplement form. While coffee, tea, and cocoa are widely known to contain caffeine, its presence in the remaining plants is not as well known to consumers, raising the likelihood of unintentional caffeine ingestion. Further, many supplements are available that include combinations of herbs containing caffeine and/or other stimulants, such as ephedrine, creating the possibility for additive or synergistic effects (45).

At normally consumed doses, caffeine is believed to mediate its stimulant effects through inhibition of adenosine receptors (46). Antagonism of presynaptic adenosine receptors causes a disinhibitory release of a variety of neurotransmitters, with a net excitatory effect. Caffeine and theophylline have proseizure effects in rats given kainic acid or Metrazol, facilitating chemically and electrically induced epileptiform activity in the CA3 region of hippocampal slices (47). Caffeine increases the amplitude of the basal field potentials from electrical stimulation of CA1 pyramidal neurons in hippocampal slices (48). Conversely, adenosine agonists reduce chemically induced epileptiform discharges, which is reversed by caffeine (49). Caffeine lengthens afterdischarges in kindled amygdaloid seizures (50). Caffeine is also used to prolong seizures induced by electroconvulsiuve therapy in patients with depression (51).



A few herbal medicines have gained a reputation for enhancing cognitive functions, particularly memory. Ginkgo is a seed-bearing tree that has characteristic fan-shaped leaves, and has a traditional reputation for improving cognition. It is perhaps the most common herb with reputed cognitive effects, and has been the subject of a fair amount of research. Research supports modest cognitive effects in patients with dementia

Cognitive Enhancer Herbs

Common name Botanical name Main active constituent

Ginkgo Ginkgo biloba Flavonoid glycosides,
terpene lactones
Ginseng Panax ginseng
Panax quinquefolium

Note. See text for references.

dementia, and preliminary support exists for effects in normal subjects (52–55). The active constituents in ginkgo are believed to be flavonoid glycosides and terpene lactones (Table 3). A definitive mechanism of action for the promnestic effects of ginkgo has not been identified; ginkgo is known to enhance cholinergic transmission (56 –58). Some ginkgo constituents, namely bilobalide, may have neuroprotective and antiseizure effects (59, 60). However these effects must be considered in the context of the total effects of total ginkgo extract, which is how it is most commonly consumed.

The U.S. Food and Drug Administration’s Special Nutritionals Adverse Event Monitoring System (SN/ AEMS) currently lists seven cases of seizures in people taking ginkgo reported by physicians (61). The preparations were all from different manufacturers, and while four involved multi-ingredient preparations, three contained only ginkgo extract. It cannot be determined whether ginkgo was causal to these cases; the database does not give details regarding dosage, any history of seizures, or whether they were worsened by taking ginkgo. This incidence of reported seizures is very small in comparison to the large numbers of people consuming ginkgo in the normal population. One case has been reported of generalized convulsions after a large dose of ginkgo nuts (62). One electrophysiological study showed that ginkgo extract causes increases in alpha and decreases in delta and theta activity in humans (63).


Ginseng typically refers to two species of plants, Asian and American ginseng (Panax ginseng and Panax quinquefolius, respectively). It has a long history of use across several cultures to treat a variety of ailments, including memory loss. Much research has been published on the promnestic effects of ginseng in animal studies, but evidence for such effects in humans is

Copyright © 2001 Elsevier Science
All rights reserved.

528 Marcello Spinella

lacking (64). The major active constituents in ginseng are a class of chemicals called the ginsenosides (65). Several mechanisms are possible for ginseng’s putative cognitive effects, but ginseng is also known to activate the hypothalamo–pituitary–adrenal axis. Ginsenosides elevate plasma ACTH and corticosteroids, and ginsenoside Rg1 is a functional ligand at the glucocorticoid receptor (66–68). Since corticosteroids have excitatory and proseizure effects, ginseng may best be avoided by those with seizure disorders (69– 71).


St. John's wort (Hypericum perforatum) is an herbal medicine with a historical reputation for treating depression. There is some empirical evidence for this effect. Meta-analyses have suggested that St. John’s wort is superior to placebo for treatment of depression of mild to moderate severity (72–74). However, one recent study has challenged these large-scale analyses (75). St. John’s wort has been shown to be equivalent to some pharmaceutical antidepressants, including fluoxetine and sertraline (76 –79). The putative antidepressant effect of St. John’s wort may be mediated by increasing monoamine activity through a variety of mechanisms (80–82). However, it also has effects on GABAergic and glutamatergic systems (82, 83).

St. John’s wort may interact pharmacokinetically with antiepileptic medications. The chemical constituent hyperforin alters drug metabolism by activation of the pregnane X receptor (84). This, in turn, alters expression of cytochrome P450 (CYP) 3A4 monooxygenase, inducing the enzyme. This has been shown to cause pharmacokinetic interactions with the drugs warfarin, digoxin, theophylline, cyclosporin, and indinavir, potentially leading to decreased efficacy (85– 89). Induction of CYP 3A4 by St. John’s wort raises the potential for interactions with phenytoin, carbamazepine, and phenobarbital. However, it does not alter clearance of carbamazepine (90). Potential interactions with phenytoin or phenobarbital have not been empirically tested.


Burkhard and colleagues (91) have reported the epileptogenic potential of the essential oils of several plants (Table 4). They present cases of three individuals with no risk factors or prior history of seizures

Herbal Essential Oils

Botanical name Epileptogenic compound

Eucalyptus Eucalyptus globulus Cineole
Fennel Foeniculum vulgare Fenchone
Hyssop Hyssopus officinalis Pinocamphone, cineole
Pennyroyal Mentha pulegium or
Hedeoma pulegioides
Rosemary Rosmarinus officinalis Cineole, camphor
Sage Salvia officinalis Thujone, camphor, cineole
Savin Juniperus sabina Sabinylacetate, camphor,
Tansy Tanacetum vulgare Thujone, camphor, cineole
Thuja Thuya occidentalis Thujone, fenchone, cineole
Turpentine Pinus species Pinenes?
Wormwood Artemisia absinthium Thujone

Source: Burkhard PR, Burkhardt K, Haenggeli CA, Landis T. Plant-induced seizures: reappearance of an old problem. J Neurol 1999;246:667–70.

who experienced generalized tonic– clonic seizures after using essential oils orally and transdermally. After discontinuation, they returned to their premorbid seizure- free status.

Plant-derived essential oils with epileptogenic effects include eucalyptus (Eucalyptus globulus), fennel (Foeniculum vulgare), hyssop (Hyssopus officinalis), pennyroyal (Mentha pulegium or Hedeoma pulegioides), rosemary (Rosmarinus officinalis), sage (Salvia officinalis), savin (Juniperus sabina), tansy (Tanacetum vulgare), thuja (Thuya occidentalis), turpentine (Pinus species), and wormwood (Artemisia absinthium). Many of these plants are commonly used as culinary spices and may seem innocuous at face value. However, as essential oils they contain concentrated amounts of compounds with established epileptogenic effects. Essential oils are sold over-the-counter, and the epileptogenic effects of certain ones are not widely known.


Evening primrose (Oenothera biennis) has become popular as a treatment for premenstrual syndrome, although experimental results have been conflicting (97). Borage (Borago officinalis) has a reputation for treating depression, inflammation, fevers, and coughs, although these uses have not been empirically tested. Both evening primrose and borage are sources of the

Copyright © 2001 Elsevier Science
All rights reserved.

Herbal Medicines and Epilepsy 529

omega-6 fatty acid g-linolenic acid (GLA) (93). GLA reportedly lowers the seizure threshold (93), although some studies report antiseizure effects of fatty acids (94, 95).


Sedative herbs such as kava and valerian may potentiate the effects of antiepileptic medications, intensifying side effects such as lethargy and cognitive impairments. Passionflower and chamomile may also have similar sedative effects in humans, although they have not been tested in humans in this regard. Kava, valerian, and passionflower have shown some antiseizure effects in animal models, but they have not been tested in humans and should not be used in place of pharmaceutical antiepileptic medications. Patients should also be advised against discontinuation of antiepileptic medications in favor of herbal remedies, since rebound seizures may occur on withdrawal of seizure medications.

Stimulant herbal medicines such as ephedra, coffee, tea, cocoa, mate´, cola, and guarana may exacerbate seizures by lowering the seizure threshold or prolonging the duration of seizures. The ubiquity of caffeine in herbal, over-the-counter preparations, and soft drink beverages may make it seem innocuous. Mate´, cola, and guarana are more recent additions to the West, and many people are unaware that they contain caffeine. Further, many over-the-counter preparations employ combinations of these drugs, creating the likelihood of additive or synergistic effects.

Potential cognitive enhancing herbal medicines such as ginkgo and ginseng may work through a variety of neurochemical mechanisms and also may exacerbate seizures under some conditions. Ginseng is known to elevate plasma levels of corticosteroid hormones, which can aggravate seizures.

St. John’s wort may alter the pharmacokinetics of some antiepileptic medications, but does not seem to affect carbamazepine. It may alter the seizure threshold, as do pharmaceutical antidepressants, but the directionality and magnitude of this are uncertain. Pharmaceutical antidepressant drugs are known to lower the seizure threshold, increasing the risk for seizures (96). However the magnitude of this risk varies with the specific antidepressant. For example, the selective serotonin reuptake inhibitors (SSRIs) exhibit low risk and may be well tolerated. To the extent that St. John’s wort interacts with monoamine, GABAergic,

and glutamatergic transmission, it may alter the seizure threshold. However, this has yet to be empirically demonstrated.

Numerous essential oils are available that contain concentrations of known epileptogenic compounds. Many of the plants from which these oils are derived are commonly used in cooking, which may obscure the potent nature of the essential oils. Evening primrose and borage have been cited to potentially lower the seizure threshold, but research in this regard is mixed and so no certain conclusions can be drawn. These herbal preparations may best be avoided until this issue is clarified.


Available evidence suggests that many herbal medicines may have the potential for adverse effects in people with seizure disorders. A combination of factors can compound this issue, including the popularity and widespread use of herbal medicines by laypersons, the reluctance of many patients to discuss their use of herbal medicines with their physicians, and a lack of knowledge about the safety and efficacy of many herbal medicines among both patients and health care providers.

Many herbal medicines are sold over-the-counter as dietary supplements, as long as they do not advertise specific claims about treatment of a disease or condition, such as obesity (97). They must have a basic level of safety for the Food and Drug Administration to allow their sale. However, an herbal medicine that may be relatively safe in the general population may also interact adversely with the symptomatic expression of medical conditions, such as epilepsy, and their treatments. Arguably, the same potential risk exists for pharmaceutical over-the-counter medications. Thus, both patients and health care providers must educate themselves on the contraindications of herbal medicines, as well as pharmaceutical medications, to avoid improper use or harmful effects. Further research is needed to establish the safety and efficacy of many herbal medicines in patients with epilepsy.


  1. Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M, Kessler RC. Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey. JAMA 1998;280:1569 –75.

Copyright © 2001 Elsevier Science
All rights reserved.

530 Marcello Spinella
  1. Peebles CT, McAuley JW, Roach J, Moore JL, Reeves AL. Alternative medicine use by patients with epilepsy. Epilepsy Behav 2000;1:74 –7.
  2. Danesi MA, Adetunji JB. Use of alternative medicine by patients with epilepsy: a survey of 265 epileptic patients in a developing country. Epilepsia 1994;35:344 –51.
  3. Frenkel M, Arye EB. The growing need to teach about complementary and alternative medicine: questions and challenges. Acad Med 2001;76:251– 4.
  4. Lebot V, Merlin M, Lindstrom L. Kava—the Pacific elixir: the definitive guide to its ethnobotany, history, and chemistry. Rochester, VT: Healing Arts Press, 1997.
  5. Pittler MII, Ernst E. Efficacy of kava extract for treating anxiety: systematic review and meta-analysis. J Clin Psychopharmacol 2000;20:84 –9.
  6. Boonen G, Haberlein H. Influence of genuine kavapyrone enantiomers on the GABA-A binding site. Planta Med 1998;64:504–6.
  7. Jussofie A, Schmiz A, Hiemke C. Kavapyrone enriched extract from Piper methysticum as modulator of the GABA binding site in different regions of rat brain. Psychopharmacology (Berlin) 1994;116:469 –74.
  8. Davies LP, Drew CA, Duffield P, Johnston GA, Jamieson DD. Kava pyrones and resin: studies on GABAA, GABAB and benzodiazepine binding sites in rodent brain. Pharmacol Toxicol 1992;712:120–6.
  9. Keledjian J, Duffield PH, Jamieson DD, Lidgard RO, Duffield AM. Uptake into mouse brain of four compounds present in the psychoactive beverage kava. J Pharm Sci 1988;77:1003– 6.
  10. Gleitz J, Beile A, Peters T. (1/2)-Kavain inhibits veratridineactivated voltage-dependent Na(1)-channels in synaptosomes prepared from rat cerebral cortex. Neuropharmacology 1995; 34:1133–8.
  11. Magura EI, Kopanitsa MV, Gleitz J, Peters T, Krishtal OA. Kava extract ingredients, (1)-methysticin and (1/2)-kavain inhibit voltage-operated Na(1)-channels in rat CA1 hippocampal eurons. Neuroscience 1997;81:345–51.
  12. Schirrmacher K, Busselberg D, Langosch JM, Walden J, Winter U, Bingmann D. Effects of (1/2)-kavain on voltage-activated inward currents of dorsal root ganglion cells from neonatal rats. Eur Neuropsychopharmacol 1999;9:171– 6.
  13. Gleitz J, Friese J, Beile A, Ameri A, Peters T. Anticonvulsive action of (1/2)-kavain estimated from its properties on stimulated synaptosomes and Na1 channel receptor sites. Eur J Pharmacol 1996;315:89 –97.
  14. Holm E, Staedt U, Heep J, Kortsik C, Behne F, Kaske A, Mennicke I. [The action profile of d,l-kavain. Cerebral sites and sleep–wakefulness-rhythm in animals]. Arzneimittelforschung 1991;41:673– 83.
  15. Frey R. [Demonstration of the central effects of d,l-kawain with EEG brain mapping]. Fortschr Med 1991;30;109:505– 8. 17. Foo H, Lemon J. Acute effects of kava, alone or in combination with alcohol, on subjective measures of impairment and intoxication and on cognitive performance. Drug Alc Rev 1997;16:147–55.
  16. Kretzschmar R, Meyer HJ, Teschendorf HJ, Zollner B. [Antagonistic action of natural 5,6-hydrogenated kava pyrones against strychnine poisoning and experimental local tetanus]. Arch Int Pharmacodyn Ther 1969;182:251– 68.
  17. Jamieson DD, Duffield PH, Cheng D, Duffield AM. Comparison of the central nervous system activity of the aqueous and lipid extract of kava (Piper methysticum). Arch Int Pharmacodyn Ther 1989;301:66–80.
  1. Gleitz J, Beile A, Peters T. (1/2)-Kavain inhibits the veratridine-and KCl-induced increase in intracellular Ca21 and glutamate-release of rat cerebrocortical synaptosomes. Neuropharmacology 1996;35:179–86.
  2. Langosch JM, Normann C, Schirrmacher K, Berger M, Walden J. The influence of (1/2)-kavain on population spikes and long-term potentiation in guinea pig hippocampal slices. Comp Biochem Physiol A 1998;120:545–9.
  3. Duffield PH, Jamieson D. Development of tolerance to kava in mice. Clin Exp Pharmacol Physiol 1991;18:571– 8.
  4. Temkin O. The falling sickness: a history of epilepsy from the Greeks to the beginnings of modern neurology. Baltimore:Johns Hopkins Univ Press, 1971.
  5. Leathwood PD, Chauffard F, Heck E, Munoz-Box R. Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man. Pharmacol Biochem Behav 1982;17:65–71.
  6. Schulz H, Stolz C, Muller J. The effect of valerian extract on sleep polygraphy in poor sleepers: a pilot study. Pharmacopsychiatry 1994;27:147–51.
  7. Gerhard U, Linnenbrink N, Georghiadou C, Hobi V. [Vigilance-decreasing effects of 2 plant-derived sedatives]. Schweiz Rundsch Med Prax 1996;85:473– 81.
  8. Houghton PJ. The scientific basis for the reputed activity of valerian. J Pharm Pharmacol 1999;51:505–12.
  9. Santos MS, Ferreira F, Faro C, Pires E, Carvalho AP, Cunha AP, Macedo T. The amount of GABA present in aqueous extracts of valerian is sufficient to account for [3H]GABA release in synaptosomes. Planta Med 1994;60:475–6.
  10. Riedel E, Hansel R, Ehrke G. [Inhibition of gamma-aminobutyric acid catabolism by valerenic acid derivatives]. Planta Med 1982;46:219–20.
  11. Ortiz JG, Nieves-Natal J, Chavez P. Effects of Valeriana officinalis extracts on [3H]flunitrazepam binding, synaptosomal [3H]GABA uptake, and hippocampal [3H]GABA release. Neurochem Res 1999;24:1373–8.
  12. Dunaev VV, Trzhetsinskii SD, Tishkin VS, Fursa NS, Linenko VI. [Biological activity of the sum of the valepotriates isolated from Valeriana alliariifolia]. Farmakol Toksikol 1987;50(6):33–7.
  13. Ho¨ lzl J, Fink C. [Effect of valeprotriate on spontaneous motor activity in mice]. Arzneimittelforschung 1984;34:44–7.
  14. Leuschner J, Muller J, Rudmann M. Characterisation of the central nervous depressant activity of a commercially available valerian root extract. Arzneimittelforschung 1993;43:638–41.
  15. Medina JH, Paladini AC, Wolfman C, Levi de Stein M, Calvo D, Diaz LE, Pena C. Chrysin (5,7-di-OH-flavone), a naturallyoccurring ligand for benzodiazepine receptors, with anticonvulsant properties. Biochem Pharmacol 1990;40:2227–31.
  16. Wolfman C, Viola H, Paladini A, Dajas F, Medina JH. Possible anxiolytic effects of chrysin, a central benzodiazepine receptor ligand isolated from Passiflora coerulea. Pharmacol Biochem Behav 1994;47:1–4.
  17. Soulimani R, Younos C, Jarmouni S, Bousta D, Misslin R, Mortier F. Behavioural effects of Passiflora incarnata L. and its indole alkaloid and flavonoid derivatives and maltol in the mouse. J Ethnopharmacol 1997;57:11–20.
  18. Medina JH, Viola H, Wolfman C, Marder M, Wasowski C, Calvo D, Paladini AC. Overview—flavonoids: a new family of benzodiazepine receptor ligands. Neurochem Res 1997;22:419–25.

Copyright © 2001 Elsevier Science
All rights reserved.

Herbal Medicines and Epilepsy 529
  1. Viola H, Wasowski C, Levi de Stein M, et al. Apigenin, a component of Matricaria recutita flowers, is a central benzodiazepine receptors-ligand with anxiolytic effects. Planta Med 1995;61:213–6.
  2. Avallone R, Zanoli P, Puia G, Kleinschnitz M, Schreier P, Baraldi M. Pharmacological profile of apigenin, a flavonoid isolated from Matricaria chamomilla. Biochem Pharmacol 2000;59:1387–94.
  3. Kalix P. The pharmacology of psychoactive alkaloids from ephedra and catha. J Ethnopharmacol 1991;32:201–8.
  4. White LM, Gardner SF, Gurley BJ, Marx MA, Wang PL, Estes M. Pharmacokinetics and cardiovascular effects of ma-huang (Ephedra sinica) in normotensive adults. J Clin Pharmacol 1997;37:116–22.
  5. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000;343:1833–8.
  6. Dhuna A, Pascual-Leone A, Langendorf F, Anderson DC. Epileptogenic properties of cocaine in humans. Neurotoxicology 1991;12:621–6.
  7. Rektor I. Influence of parenterally administered amphetamine on the paroxysmal EEG activity in epileptics. Physiol Bohemoslov 1984;33:43–8.
  8. Young R, Gabryszuk M, Glennon RA. (2)Ephedrine and caffeine mutually potentiate one another’s amphetamine-like stimulus effects. Pharmacol Biochem Behav 1998;61:169–73.
  9. Snyder SH, Sklar P. Behavioral and molecular actions of caffeine: focus on adenosine. J Psychiatr Res 1984;18:91–106.
  10. Ault B, Olney MA, Joyner JL, Boyer CE, Notrica MA, Soroko FE, Wang CM. Proconvulsant actions of theophylline and caffeine in the hippocampus: implications for the management of temporal lobe epilepsy. Brain Res 1987;426:93–102.
  11. Frank C, Sagratella S, Benedetti M, Scotti de Carolis A. Comparative influence of calcium blocker and purinergic drugs on epileptiform bursting in rat hippocampal slices. Brain Res 1988;441:393–7.
  12. Tancredi V, D’Antuono M, Nehlig A, Avoli M. Modulation of epileptiform activity by adenosine A1 receptor-mediated mechanisms in the juvenile rat hippocampus. J Pharmacol Exp Ther 1998;286:1412–9.
  13. Albertson TE, Joy RM, Stark LG. Caffeine modification of kindled amygdaloid seizures. Pharmacol Biochem Behav 1983; 19:339–43.
  14. Coffey CE, Figiel GS, Weiner RD, Saunders WB. Caffeine augmentation of ECT. Am J Psychiatry 1990;147:579–85.
  15. Field B, Vadnal R. Ginkgo biloba and memory: an overview. Nutr Neurosci 1998;1:2565–7.
  16. Oken BS, Storzbach DM, Kaye JA. The efficacy of ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol 1998;55:1409–15.
  17. Subhan Z, Hindmarch I. The psychopharmacological effects of ginkgo biloba extract in normal healthy volunteers. Int J Clin Pharmacol Res 1984;4:89–93.
  18. Warot D, Lacomblez L, Danjou P, Weiller E, Payan C, Puech AJ. [Comparative effects of Ginkgo biloba extracts on psychomotor performances and memory in healthy subjects]. Therapie 1991;46:33–6.
  19. Kristofikova Z, Benesova O, and Tejkalova H. Changes in high-affinity choline uptake in the hippocampus of old rats after long-term administration of two nootropic drugs (tacrine and ginkgo biloba extract). Dementia 1992;3:304–7.
  1. Kristofikova Z, Klaschka J. In vitro effect of ginkgo biloba extract (EGb 761) on the activity of presynaptic cholinergic nerve terminals in rat hippocampus. Dement Geriatr Cogn Disord 1997;8:43–8.
  2. Taylor JE. [Neuromediator binding to receptors in the rat brain: the effect of chronic administration of ginkgo biloba extract]. Presse Med 1986;15:1491–3.
  3. Weichel O, Hilgert M, Chatterjee SS, Lehr M, Klein J. Bilobalide, a constituent of ginkgo biloba, inhibits NMDA-induced phospholipase A2 activation and phospholipid breakdown in at hippocampus. Naunyn Schmiedebergs Arch Pharmacol 1999;360:609–15.
  4. Sasaki K, Wada K, Hatta S, Ohshika H, Haga M. Bilobalide, a constituent of ginkgo biloba L., potentiates drug-metabolizing enzyme activities in mice: possible mechanism for anticonvulsant activity against 4-O-methylpyridoxine-induced convulsions. Res Commun Mol Pathol Pharmacol 1997;96:45–56.
  5. Gregory PJ. Seizure associated with Ginkgo biloba? Ann Intern Med 2001;134:344.
  6. Miwa H, Iijima M, Tanaka S, Mizuno Y. Generalized convulsions after consuming a large amount of gingko nuts. Epilepsia 2001;42(2):280–1.
  7. Itil TM, Eralp E, Ahmed I, Kunitz A, Itil KZ. The pharmacological effects of Ginkgo biloba, a plant extract, on the brain of dementia patients in comparison with tacrine. Psychopharmacol Bull 1998;34:391–7.
  8. Vogler BK, Pittler MH, Ernst E. The efficacy of ginseng: a systematic review of randomised clinical trials. Eur J Clin Pharmacol 1999;55:567–75.
  9. Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58:1685–93.
  10. Hiai S, Yokoyama H, Oura H, Yano S. Stimulation of pituitary–adrenocortical system by ginseng saponin. Endocrinol Jpn 1979;26:661–5.
  11. Zhang JT, Qu ZW, Liu Y, Deng HL. Preliminary study on antiamnestic mechanism of ginsenoside Rg1 and Rb1. Chin Med J (Engl) 1990;103:932–8.
  12. Lee YJ, Chung E, Lee KY, Lee YH, Huh B, Lee SK. Ginsenoside-Rg1, one of the major active molecules from Panax ginseng, is a functional ligand of glucocorticoid receptor. Mol Cell Endocrinol 1997;133:135–40.
  13. Temkin NR, Davis GR. Stress as a risk factor for seizures among adults with epilepsy. Epilepsia 1984;25:450–6.
  14. Karst H, de Kloet ER, Joels M. Episodic corticosterone treatment accelerates kindling epileptogenesis and triggers longterm changes in hippocampal CA1 cells, in the fully kindled state. Eur J Neurosci 1999;11:889–98.
  15. Roberts AJ, Crabbe JC, Keith LD. Type I corticosteroid receptors modulate PTZ-induced convulsions of withdrawal seizure prone mice. Brain Res 1993;626:143–8.
  16. Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D. St John’s wort for depression—an overview and meta-analysis of randomised clinical trials. Br Med J 1996;313:253–8.
  17. Kim HL, Streltzer J, Goebert D. St. John’s wort for depression: a meta analysis of well-defined clinical trials. J Nerv Ment Dis 1999;187:532–8.
  18. Linde K, Mulrow CD. St John’s wort for depression. Cochrane Database Syst Rev 2000;(2):CD000448.

Copyright © 2001 Elsevier Science
All rights reserved.

530 Marcello Spinella
  1. Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St John’s wort in major depression: a randomized controlled trial. JAMA 2001;285:1978–86.
  2. Schrader E. Equivalence of St John’s wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild–moderate depression. Int Clin Psychopharmacol 2000;2:61–8.
  3. Volz HP, Laux P. Potential treatment for subthreshold and mild depression: a comparison of St. John’s wort extracts and fluoxetine. Compr Psychiatry 2000;41:S133–7.
  4. Harrer G, Schmidt U, Kuhn U, Biller A. Comparison of equivalence between the St. John’s wort extract LoHyp-57 and fluoxetine. Arzneimittelforschung 1999;49:289–96.
  5. Brenner R, Azbel V, Madhusoodanan S, Pawlowska M. Comparison of an extract of hypericum (LI 160) and sertraline in the treatment of depression: a double-blind, randomized pilot study. Clin Ther 2000;22:411–9.
  6. Bennett DA, Phun L, Polk JF, Voglino SA, Zlotnik V, Raffa RB. Neuropharmacology of St. John’s Wort (Hypericum). Ann Pharmacother 1998;32:1201–8.
  7. Singer A, Wonnemann M, Mu¨ ller WE. Hyperforin, a major antidepressant constituent of St. John’s Wort, inhibits serotonin uptake by elevating free intracellular Na11. J Pharmacol Exp Ther 1999;290:1363–8.
  8. Nathan PJ. Hypericum perforatum (St John’s Wort): a non-selective reuptake inhibitor? A review of the recent advances in its pharmacology. J Psychopharmacol 2001;15:47–54.
  9. Cott JM. In vitro receptor binding and enzyme inhibition by Hypericum perforatum extract. Pharmacopsychiatry 1997;30(suppl 2):108–12.
  10. Moore LB, Goodwin B, Jones SA, et al. St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 2000;97:7500–2.
  11. Nebel A, Schneider BJ, Baker RK, Kroll DJ. Potential metabolic interaction between St. John’s wort and theophylline. Ann Pharmacother 1999;33:502.
  1. Ruschitzka F, Meier PJ, Turina M, Luscher TF, Noll G. Acute heart transplant rejection due to Saint John’s wort. Lancet 2000;355:548–9.
  2. Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich M, Roots I. Pharmacokinetic interaction of digoxin with an herbal extract from St John’s wort (Hypericum perforatum). Clin Pharmacol Ther 1999;66:338–45.
  3. Yue QY, Bergquist C, Gerden B. Safety of St John’s wort (Hypericum perforatum). Lancet 2000;355:576–7.
  4. Miller JL. Interaction between indinavir and St. John’s wort reported. Am J Health Syst Pharm 2000;57:625–6.
  5. Burstein AH, Horton RL, Dunn T, Alfaro RM, Piscitelli SC, Theodore W. Lack of effect of St John’s Wort on carbamazepine pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 2000;68:605–12.
  6. Burkhard PR, Burkhardt K, Haenggeli CA, Landis T. Plantinduced seizures: reappearance of an old problem. J Neurol 1999;246:667–70.
  7. Bendich A. The potential for dietary supplements to reduce premenstrual syndrome (PMS) symptoms. J Am Coll Nutr 2000;19:3–12.
  8. Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug–herb interactions. Arch Intern Med 1998;158:2200–11.
  9. Voskuyl RA, Vreugdenhil M, Kang JX, Leaf A. Anticonvulsant effect of polyunsaturated fatty acids in rats, using the cortical stimulation model. Eur J Pharmacol 1998;341:145–52.
  10. Yehuda S, Carasso RL, Mostofsky DI. Essential fatty acid preparation (SR-3) raises the seizure threshold in rats. Eur J Pharmacol 1994;254:193–8.
  11. Alldredge BK. Seizure risk associated with psychotropic drugs: clinical and pharmacokinetic considerations. Neurology 1999;53:S68–75.
  12. Dietary Supplement Health and Education Act of 1994. 1994; Pub L No. 103–417.

Copyright © 2001 Elsevier Science
All rights reserved.

Authored Date: 
Wednesday, November 6, 2013