Herbal Treatments in Epilepsy

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Herbal Treatments in Epilepsy

• F.A.C.E.S. Evening Lecture Series
• June 16, 2009
• Siddhartha S. Nadkarni, M.D.

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• and yes I said yes I will yes

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• if it was out there we wouldnt be having this
  talk.

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• 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.

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Editorial

• Randomized Controlled Blinded trials
• Doctors and patients are both biased
• Placebo effect is not nothing
• RCTs are our best method to date to assess
  efficacy given how much we dont know about the
  brain
• Double blind
• Anecdote Vs. Parachute
• The power of mind (placebo revisited)

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Complimentary and Alternative

• CAM
• On the rise
• 42 US
• 65 Germany
• 20 UK
• 1/6 people taking Rx also take Herbal
• gt 50 y.o. 2.66 herbals and 2.26 Rx

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CAM

• lt 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

• 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
• 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, gt75
  seizure reduction in 66 and gt 50 in another 30
• (Tyagi et al, 2003)

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• 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

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• Vincent Van Gogh
• 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

• Wormwood (artemesia absinthium)
• Used to distill alcohol
• Contains terpene thujone, a proconvulsant
• Had Hallucinatory convulsions

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Herbal Therapies
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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

• Ladys 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

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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 19982801569-75.
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How often do people take herbs?
Top 10 selling herbs and dietary supplements 2002
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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. Johns wort,
  melatonin, gingko biloba, garlic and black cohosh
• Treat seizures (lt10), other symptoms (20), and
  general health (gt70)

Peebles et al. Epilepsy Behav 2000174-7 Easterfo
rd et al. Epilepsy Behav 2005659-62
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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.
• Hasnt mentioned symptoms to doctor.
• St. Johns wort is an herb for mild depression.

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Case Presentation, cont.

• You go to a health foods store and look at
  different bottles of St. Johns wort.

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Case Presentation, cont.

• 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. Johns wort, as it does for the
  testing and manufacturing of prescription drugs?

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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.

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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

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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

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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

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Case Presentation, cont.

• What do the disclaimers mean?
• What about their quality, whether the FDA
  controls the testing of St. Johns wort?, how is
  it manufactured?
• What about the amount of active ingredients?

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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

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? 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
  

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Case Presentation, cont.

• You wonder whether St. Johns 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

• 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

• Dont use Valerian or Kava with alcohol,
  barbiturates, benzos- sedation/coma.
• Hemorrhagic complications with Gingko and St.
  Johns wort.
• St. Johns 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

• Increase Side effects
• Valerian Root
• Kava Kava
• Passion Flower
• Chamomile

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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.

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Herbs and seizures

• Worsen seizures
• Ephedra
• Ma Huang
• Mate
• Guarana
• Borage oil
• ? Ginkgo
• ? Ginseng

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Side-Effects of Herbs

• Natural doesnt 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
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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

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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

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Melatonins Effects

• Anti-oxidant
• Blocks effects of glutamate (neuroprotective)
• Enhances GABA actions

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Clinical Use of Melatonin in Epilepsy Patients

• Given orally 30-60 minutes before bedtime
• Dose ranges from 1-10 mg

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Herbal Issues

• Good
• Bad
• Ugly

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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

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Bad

• Effects on Serum Concentration of AEDs
  (Herb-Drug interactions) P450 enzymes
• St. Johns wort
• Garlic
• Echinacea
• Pine bark extract
• Pygenol
• Milk thistle
• American hellebore
• Gingko
• Mugwort
• Pipissewa

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Samuels et al, 2008
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Ugly

• 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
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Samuels et al, 2008
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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

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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.

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• Canada
• Alaska
• Arizona
• California
• Colorado
• Hawaii
• Maine
• Nevada
• Oregon
• Rhode Island
• Vermont
• Washington

Alfred Nobel
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• Contains approximately 60 active substances
• Primary active chemicals
• Delta 9 tetrahydrocannibinol
• Delta 8 tetrahydrocannibinol
• Cannabidiol

Edgar Allen Poe
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• 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

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• Evidence that endocannabinoid system facilitates
  neuroprotective activity at baseline
• The system appears to be upregulated in response
  to various brain insults.

Neil Young
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• ? 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

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• Long term effects of cannaboids?
• Impaired memory
• Marijuana amotivational syndrome

Lenin
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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

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Gross et al, 2004
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Gross et al, 2004
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• 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

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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