Herbal medicines and epilepsy: the potential for benefit and adverse effects
Herbal Medicines and Epilepsy: The Potential for Benefit and Adverse Effects
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:
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).
Copyright © 2001 Elsevier Science
All rights reserved.
|Herbal Medicines and Epilepsy
||Main active constituent
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
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-
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
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).
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
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-
||Main active constituent
||Caffeine, Theophylline, Theobromine
|Note. See text for references.
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).
|Herbal Medicines and Epilepsy
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).
HERBAL COGNITIVE ENHANCERS
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
||Main active constituent
|Note. See text for references.
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
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
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–
ST. JOHN'S WORT
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
HERBAL ESSENTIAL OILS
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
||Mentha pulegium or
||Thujone, camphor, cineole
||Thujone, camphor, cineole
||Thujone, fenchone, cineole
|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-
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.
OTHER HERBAL MEDICINES: EVENING PRIMROSE AND BORAGE
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
|Herbal Medicines and Epilepsy
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
IMPLICATIONS FOR PATIENTS WITH EPILEPSY
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
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
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.
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