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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.

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Herbal treatments in epilepsy l.jpg

Herbal Treatments in Epilepsy

F.A.C.E.S. Evening Lecture Series

June 16, 2009

Siddhartha S. Nadkarni, M.D.




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Editorial l.jpg
Editorial surgery to remove the “stone” that was causing sz. There would be a cross shaped incision made in the back of the head.

  • 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)


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Complimentary and Alternative surgery to remove the “stone” that was causing sz. There would be a cross shaped incision made in the back of the head.

  • 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


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CAM surgery to remove the “stone” that was causing sz. There would be a cross shaped incision made in the back of the head.

  • < 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


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CAM and Epilepsy surgery to remove the “stone” that was causing sz. There would be a cross shaped incision made in the back of the head.

  • 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.


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  • Herb: surgery to remove the “stone” that was causing sz. There would be a cross shaped incision made in the back of the head.

    • 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…


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  • 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)


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  • Japanese Kampo medicine seizure control as adjunct treatment in 9/32 patients

    • 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


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    • Vincent Van Gogh seizure control as adjunct treatment in 9/32 patients

    • Complicated birth history, family history, pip, etc.

    • “Sorrow is eternal.” His last words spoken to his brother on his deathbed.


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    Van Gogh and Herbs seizure control as adjunct treatment in 9/32 patients

    • Wormwood (artemesia absinthium)

    • Used to distill alcohol

    • Contains terpene thujone, a proconvulsant

    • Had Hallucinatory convulsions


    Herbal therapies l.jpg
    Herbal Therapies seizure control as adjunct treatment in 9/32 patients


    Herbs for epilepsy l.jpg

    Valerian root seizure control as adjunct treatment in 9/32 patients

    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

    Herbs for Epilepsy


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    How often do people take herbs? seizure control as adjunct treatment in 9/32 patients

    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.


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    How often do people take herbs? seizure control as adjunct treatment in 9/32 patients

    Top 10 selling herbs and dietary supplements: 2002


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    How often do persons with epilepsy take herbs? seizure control as adjunct treatment in 9/32 patients

    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 l.jpg
    Case Presentation seizure control as adjunct treatment in 9/32 patients

    • 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.


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    Case Presentation, cont. seizure control as adjunct treatment in 9/32 patients

    You go to a health foods store and look at different bottles of St. John’s wort.


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    Case Presentation, cont. seizure control as adjunct treatment in 9/32 patients

    • 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?


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    Federal regulation of herbs seizure control as adjunct treatment in 9/32 patients

    • 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.


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    Federal standards by DSHEA seizure control as adjunct treatment in 9/32 patients

    • 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


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    Federal regulation of herbs seizure control as adjunct treatment in 9/32 patients

    • 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


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    Federal regulation of herbs seizure control as adjunct treatment in 9/32 patients

    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


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    Case Presentation, cont. seizure control as adjunct treatment in 9/32 patients

    • 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?


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    Standardization seizure control as adjunct treatment in 9/32 patients

    • 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


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    ? The active ingredient seizure control as adjunct treatment in 9/32 patients

    • St. John's wort standardized by its content of hypericin (typically to 0.3% hypericin)

    • Hypericin not confirmed as the active ingredient


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    Case Presentation, cont. seizure control as adjunct treatment in 9/32 patients

    You wonder whether St. John’s wort could affect your carbamazepine or birth control pill, and whether it is safe and actually helps depression


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    Herbal Anticonvulsants: Mechanisms seizure control as adjunct treatment in 9/32 patients

    • 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)


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    Herb/AED Interactions seizure control as adjunct treatment in 9/32 patients

    • 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.


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    Herbs and Seizure Medications seizure control as adjunct treatment in 9/32 patients

    • Increase Side effects

      • Valerian Root

      • Kava Kava

      • Passion Flower

      • Chamomile


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    Herbs that cause Seizures seizure control as adjunct treatment in 9/32 patients

    • 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 l.jpg
    Herbs and seizures seizure control as adjunct treatment in 9/32 patients

    • Worsen seizures

      • Ephedra

      • Ma Huang

      • Mate

      • Guarana

      • Borage oil

      • ? Ginkgo

      • ? Ginseng


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    Side-Effects of Herbs seizure control as adjunct treatment in 9/32 patients

    • 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.


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    Herbal Therapies seizure control as adjunct treatment in 9/32 patients


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    Traditional Chinese Herbal Medicine (TCHM) seizure control as adjunct treatment in 9/32 patients

    • 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


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    Melatonin seizure control as adjunct treatment in 9/32 patients

    • 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


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    Melatonin’s Effects seizure control as adjunct treatment in 9/32 patients

    • Anti-oxidant

    • Blocks effects of glutamate (neuroprotective)

    • Enhances GABA actions


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    Clinical Use of Melatonin in Epilepsy Patients seizure control as adjunct treatment in 9/32 patients

    • Given orally 30-60 minutes before bedtime

    • Dose ranges from 1-10 mg


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    Herbal Issues seizure control as adjunct treatment in 9/32 patients

    • Good

    • Bad

    • Ugly


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    Good seizure control as adjunct treatment in 9/32 patients

    • 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


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    Bad seizure control as adjunct treatment in 9/32 patients

    • 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


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    Samuels et al, 2008 seizure control as adjunct treatment in 9/32 patients


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    Ugly seizure control as adjunct treatment in 9/32 patients

    • Many herbs have been reported to be pro-convulsants

    • These are both in laboratory/mice models and in case reports in humans


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    Samuels et al, 2008 seizure control as adjunct treatment in 9/32 patients


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    Samuels et al, 2008 seizure control as adjunct treatment in 9/32 patients


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    Data seizure control as adjunct treatment in 9/32 patients

    • 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


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    Case Study seizure control as adjunct treatment in 9/32 patients

    • 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.


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    Alfred Nobel seizure control as adjunct treatment in 9/32 patients

    Canada

    Alaska

    Arizona

    California

    Colorado

    Hawaii

    Maine

    Nevada

    Oregon

    Rhode Island

    Vermont

    Washington


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    Edgar Allen seizure control as adjunct treatment in 9/32 patients

    Poe

    • Contains approximately 60 active substances

    • Primary active chemicals:

      • Delta 9 tetrahydrocannibinol

      • Delta 8 tetrahydrocannibinol

      • Cannabidiol


    Slide62 l.jpg

    • G-protein coupled cannabinoid CB1 receptors seizure control as adjunct treatment in 9/32 patients

    • Abundantly distributed in the BG, cerebellum, limbic system and cortex

    • Endocanabinoids act as retrograde messengers at many central synapses causing inhibition of neurotransmitter release


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    Neil Young seizure control as adjunct treatment in 9/32 patients

    • Evidence that endocannabinoid system facilitates neuroprotective activity at baseline

    • The system appears to be upregulated in response to various brain insults.


    Slide64 l.jpg

    ? 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


    Slide65 l.jpg

    Lenin generalized epilepsy

    Long term effects of cannaboids?

    • Impaired memory

    • Marijuana amotivational syndrome


    Marijuana l.jpg
    Marijuana generalized epilepsy

    • 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


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    Gross et al, 2004 generalized epilepsy


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    Gross et al, 2004 generalized epilepsy


    Slide70 l.jpg


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    Take Home generalized epilepsy

    • 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


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