Transcript Herbal Treatments in Epilepsy

Herbal Treatments in Epilepsy
F.A.C.E.S. Evening Lecture
Series
June 16, 2009
Siddhartha S. Nadkarni, M.D.
and yes I said yes I will yes
if it was out there we wouldn’t be having
this talk.
• Stone cutters were
quacks in the middle
ages who would do
surgery to remove
the “stone” that was
causing sz. There
would be a cross
shaped incision
made in the back of
the head.
Editorial
• Randomized Controlled Blinded trials:
– Doctors and patients are both biased
– Placebo effect is not nothing
– RCT’s are our best method to date to
assess efficacy given how much we don’t
know about the brain
– Double blind
– Anecdote Vs. Parachute
– The power of mind (placebo revisited)
Complimentary and
Alternative
• CAM
– On the rise
– 42% US
– 65% Germany
– 20% UK
– 1/6 people taking Rx also take Herbal
– > 50 y.o.: 2.66 herbals and 2.26 Rx
CAM
• < 40% share their use with Drs.
• Legislation requiring regulation/licensing
of Herbs in Germany, France, Sweden,
Australia.
• In US the Dietary Supplement Health
and Education Act of 1994 removed
these products from FDA jurisdiction
CAM and Epilepsy
• Ohio study of 92 patients:
– 24% using CAM
– Of which 41% used herbs
• Nigerian study of 265 patients:
– 47.6% using only traditional African med.
• Herb:
– 1.) a seed producing annual, biennial, or
perennial that does not develop persistent
woody tissue but dies down at the end fo a
growing season
– 2.) a plant or plant part valued for its
medicinal, savory, or aromatic qualities
– 3.) slang…
• Qingyangsen roots – open label study showing improved seizure
control as adjunct treatment in 9/32 patients
– Postulated in one animal study that when used in
combination with PTN may reduce early production of fos
protein
• 13 Herb mixture (100pt) compared to phenobarbital control (40
pt)- open label study, similar efficacy with decreased side effects
• Zhenxiangling (main ingredients peach flower buds and human
placenta)- open label study, >75 % seizure reduction in 66% and
> 50% in another 30%
(Tyagi et al, 2003)
• Japanese Kampo medicine
• TJ- 690 (mixture of 9 herbs)- small trial (26pt)
showing improvement in seizure control and
cognitive function
• Indian Ayurvedic medicine
• Ashwagandha, Brahmirasayan and
Brahmigritham have been used for centuries
to control seizures
• Mentat (BR-16A) widely used in conjunction
with AEDS in current Indian practice
– Decreases Phenytoin metabolism and
increases bioavailability of Carbamazepine
• Vincent Van Gogh
• Complicated birth history, family history, pip, etc.
• “Sorrow is eternal.” His last words spoken to his
brother on his deathbed.
Van Gogh and Herbs
• Wormwood (artemesia absinthium)
• Used to distill alcohol
• Contains terpene thujone, a
proconvulsant
• Had Hallucinatory convulsions
Herbal Therapies
Herbs for Epilepsy
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Valerian root
Skullcap
European Mistletoe
Marijuana
Black cohosh
Lobelia
Kava
Hyssop
Blue vervain
Yarrow
Geranium
Kelp
Bupleurum
Passion flower
Carline thistle
Elderberry
Mugwort
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Lady’s slipper
Aloe
Betony
European Peony
Ginseng
Flax seed oil
Ginger
Linden
Chrysanthemum
Forskolin
Behen
Burning bush
Calotropis
Gotu Kola
Groundsel
Lily of the Valley
Tree of Heaven
Yew
How often do people take
herbs?
Overall use of complementary and alternative
medicines (CAM) in U.S. 1990-1997.
•
•
•
Herbal product use increased 4x
In 1997, adults - 33 million office visits regarding herbal
products & high-dose vitamins; spent ~$8 billion
In 1997, ~15 million adults took prescription medications with
herbs and/or high-dose vitamins
Eisenberg et al. JAMA 1998;280:1569-75.
How often do people take
herbs?
Herb
Top 10 selling
herbs and
dietary
supplements:
2002
U.S. sales
($ millions)
Gingko biloba
150
Echinacea
70
Garlic
50
Ginseng
40
Soy
35
Saw palmetto
30
St. John’s wor
30
Valerian
16
How often do persons with epilepsy
take herbs?
U.S. and England studies:
•
Up to 1 in 3 persons with epilepsy use CAM
•
Most do not discuss their CAM use with doctors
•
Herbs taken include ginseng, St. John’s wort, melatonin,
gingko biloba, garlic and black cohosh
•
Treat seizures (<10%), other symptoms (20%), and
general health (>70%)
Peebles et al. Epilepsy Behav 2000;1:74-7
Easterford et al. Epilepsy Behav 2005;6:59-62
Case Presentation
1. 35-year-old woman with epilepsy for 18 years, on
carbamazepine and an oral contraceptive.
2. For several months, feeling depressed, though
functions well day to day.
3. Hasn’t mentioned symptoms to doctor.
4. St. John’s wort is an herb for mild depression.
Case Presentation, cont.
You go to a health foods store and look at
different bottles of St. John’s wort.
Case Presentation, cont.
1. What do the disclaimers on the labels
mean?
2. What about the quality of the products
1. Does the FDA control the manufacturing and
testing of St. John’s wort, as it does for the
testing and manufacturing of prescription
drugs?
Federal regulation of herbs
•
•
Herbal products are classified by the
government as dietary supplements.
Dietary supplements are regulated by the 1994
Dietary Supplement and Health Education Act
(DSHEA); prescription drugs - much more
rigorous requirements of the Federal Food,
Drug, and Cosmetic Act.
Federal standards by DSHEA
• Claim -- an effect on bodily structure
or function, not against a specific
disease.
• Label must include a disclaimer that
FDA has not evaluated the product
Federal regulation of herbs
•
•
•
•
Not required to be produced under Good
Manufacturing Process standards, like drugs
No government agency (eg, FDA)
independently verifies the quality/production
Could be contaminated with microbes,
pesticides, toxic metals, or adulterated (eg,
herbs or drugs)
Potency and amount per pill/capsule may vary
significantly within the same bottle or from
batch to batch, or from one branded product to
another
Federal regulation of herbs
Standards set forth by the DSHEA:
• Manufacturers are responsible for the
truthfulness of labeling claims
• No government agency independently reviews
and verifies the claims and supporting
evidence
• Only manufacturers control product quality and
verify safety
Case Presentation, cont.
1. What do the disclaimers mean?
2. What about their quality, whether the
FDA controls the testing of St. John’s
wort?, how is it manufactured?
3. What about the amount of active
ingredients?
Standardization
•
•
•
How much of the active ingredient?
For example, bottle says “carbamazepine 200 mg”
This is a major problem for herbal products because
–
–
–
the active ingredient (s) are usually not known
the amount of the assumed active ingredient may vary from pill
to pill and product to product
it is usually not possible to measure levels in the blood to
guide dosage
? The active ingredient
•
•
St. John's wort standardized by its content of hypericin
(typically to 0.3% hypericin)
Hypericin not confirmed as the active ingredient
Case Presentation, cont.
You wonder whether St. John’s wort could
affect your carbamazepine or birth control
pill, and whether it is safe and actually
helps depression
Herbal Anticonvulsants:
Mechanisms
• Sedative effect/improved sleep:
Valerian, Kava, Lobelia, passion flower.
• Increase in brain GABA/GABA
receptors (Valerian, Kava)
• Agonist of benzodiazepine receptors
(Passion flower).
• Antioxidants (TJ-960)
Herb/AED Interactions
• Don’t use Valerian or Kava with alcohol,
barbiturates, benzos- sedation/coma.
• Hemorrhagic complications with Gingko and
St. John’s wort.
• St. John’s wort can lower carbamazepine
levels.
• Shankapulshpi (Ayurvedic formula)
decreases 1/2 life of phenytoin and
decreases its efficacy.
• Tell your physician about herb use; anticipate
potential for interactions.
Herbs and Seizure
Medications
• Increase Side effects
– Valerian Root
– Kava Kava
– Passion Flower
– Chamomile
Herbs that cause Seizures
•
•
•
•
•
•
•
•
•
Kava Kava: GTC from toxicity and withdrawal.
Marijuana: intoxication or withdrawal.
Skullcap: confusion and convulsions with high doses.
Ma Huang: has ephedrine, pseudoephedrine, lowers threshold.
Gamolenic acid lowers seizure threshold: evening primrose oil,
borage (starflower).
Goldenseal: hydrastine lowers threshold.
Ginseng: lowers threshold.
Ginkgo biloba: GTCs reported. Neurotoxin 4’-omethylpyridoxine.
Thujone-containing herbs: wormwood, sage; lower threshold.
Herbs and seizures
• Worsen seizures
– Ephedra
– Ma Huang
– Mate
– Guarana
– Borage oil
– ? Ginkgo
– ? Ginseng
Side-Effects of Herbs
• Natural doesn’t equal safe!
• Herbs and herbal preparations contain
many compounds.
• Black cohosh, Valerian, green tea have
tannins - can affect absorption of Ca,
Cu, Fe, Mg.
• Black cohosh can cause miscarriage via
uterine stimulation.
• Lobelia - respiratory paralysis and
death.
Herbal Therapies
Traditional Chinese Herbal
Medicine (TCHM)
•
•
•
•
Epilepsy therapy since 770 B.C.
Principles of “Yin Yang Wu Xing”
No well controlled studies
Numerous laboratory studies show
antiepileptic effects for many
• Many preparations are compound
Melatonin
•
•
•
•
Natural hormone
Promotes sleep
Used in various neurological conditions
Antiseizure properties reported clinically
in humans (small series, anecdotes)
and dogs (nocturnal seizures) and
experimentally in rodents
Melatonin’s Effects
• Anti-oxidant
• Blocks effects of glutamate
(neuroprotective)
• Enhances GABA actions
Clinical Use of Melatonin in
Epilepsy Patients
• Given orally 30-60 minutes before
bedtime
• Dose ranges from 1-10 mg
Herbal Issues
• Good
• Bad
• Ugly
Good
• Our bias in Western Medicine is
entrenched and should always be in
front of our eyes
• Ancient traditions often survive for the
efficacy of their system and treatments:
– Ayurveda
– Chinese Medicine
Bad
• Effects on Serum Concentration of AED’s
(Herb-Drug interactions) P450 enzymes:
–
–
–
–
–
–
–
–
–
–
St. John’s wort
Garlic
Echinacea
Pine bark extract
Pygenol
Milk thistle
American hellebore
Gingko
Mugwort
Pipissewa
Samuels et al, 2008
Ugly
• Many herbs have been reported to be
pro-convulsants
• These are both in laboratory/mice
models and in case reports in humans
Samuels et al, 2008
Samuels et al, 2008
Data
• As of 2005:
– 3 randomized controlled trials
– 5 non-randomized controlled trials
– 6 case control studies
– 57 observational studies, case reports
– Only one since 2005 of herbs in epilepsy
– 135 herbs
– Poorly done studies
Case Study
• 27 y.o. woman with frequent auras and
monthly complex partial seizures who is
exquisitely sensitive to medication asks
her doctor about Marijuana. She says
her father had refractory seizures until
he moved to Toronto where he could
get it freely and has been seizure free
since taking it regularly.
•
•
•
•
•
•
•
•
•
•
•
•
Canada
Alaska
Arizona
California
Colorado
Hawaii
Maine
Nevada
Oregon
Rhode Island
Vermont
Washington
Alfred Nobel
• Contains approximately 60 active
substances
• Primary active chemicals:
– Delta 9 tetrahydrocannibinol
– Delta 8 tetrahydrocannibinol
– Cannabidiol
Edgar Allen
Poe
•
G-protein coupled
cannabinoid CB1
receptors
• Abundantly distributed in
the BG, cerebellum,
limbic system and cortex
• Endocanabinoids act as
retrograde messengers
at many central
synapses causing
inhibition of
neurotransmitter release
• Evidence that endocannabinoid system
facilitates neuroprotective activity at
baseline
• The system appears to be upregulated
in response to various brain insults.
Neil Young
• ? THC beneficial in partial epilepsy and
detrimental in generalized epilepsy
• ? CBD more of anticonvulsant
• One epidemiologic study of drug use
and new onset seizures found that
marijuana may be protective against first
seizures in men
Long term effects of
cannaboids?
- Impaired memory
- Marijuana amotivational
syndrome
Lenin
Marijuana
• First used as antiepileptic in 19th century.
• Cannabinoid receptors in brainstem, limbic system,
cortex.
• Mixed results
• THC has anti- or proconvulsant affects depending on
dose and epilepsy model.
• Many cannibiols - variable effects
• Epidemiologic study- may be protective against first
seizures in men
• Has other potentially negative health consequences
(e.g., cardiovascular, pulmonary). ?? withdrawal
seizures.
• Illegal and therefore cannot be prescribed except for
states with medical marijuana
Gross et al, 2004
Gross et al, 2004
• There are likely some who will benefit
from THC
• There are likely some who will have
worsening seizures from THC
• Other effects of THC most likely
outweigh benefits in most cases
Take Home
• In any given person herbs may be helpful, but
in most they likely are not
• In any given person herbs may worsen
epilepsy
• Herbs definitely can effect AED levels
• No good studies
• Communication between doctors and patients
is crucial
• Perspective