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 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:

How often do people take herbs? HerbU.S. sales ($ millions) Gingko biloba150 Echinacea70 Garlic50 Ginseng40 Soy35 Saw palmetto30 St. John’s wor30 Valerian16 Top 10 selling herbs and dietary supplements: 2002

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 ( 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’-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 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