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? Top 10 selling herbs and dietary supplements: 2002 Herb 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
35-year-old woman with epilepsy for 18 years, on carbamazepine and an oral contraceptive.
For several months, feeling depressed, though functions well day to day.
Hasn’t mentioned symptoms to doctor.
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.

What do the disclaimers on the labels mean?
What about the quality of the products
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

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

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

What do the disclaimers mean?
What about their quality, whether the FDA controls the testing of St. John’s wort?, how is it manufactured?
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

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’-o-methylpyridoxine.
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

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

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

Herbal Treatments In Epilepsy

by A.J. Lawrence on Nov 24, 2009

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