03 saturday morning 10-25-14

Medical Marijuana &

Epilepsy

Derek J Chong, MD, MScAssistant Professor of Neurology

NYU Comprehensive Epilepsy Center

TerminologyCannabis: is the latin name (derived from the Greek Kánnabis for ‘hemp’). It is the scientific term as of 1700’s. Used by botanists and pharmaceutical companies since.

Marijuana: generally refers to the leaves and female flowers (buds) of the cannabis plant. Name derived in USA, from Mexican immigrants who used the term “Mariguana”. Primarily used in negative advertisements in 1930’s to sound ‘foreign’ and ‘dangerous’, also termed ‘locoweed’.

Hashish: derived from “grass” (Arabic), from glands off the Cannabis stalks - a resin

Hemp: is the Cannabis plant, but refers to one grown for purely industrial purposes and has minimal quantities of psychoactive substances (the bare stalks used primarily - rope)

Cannabinoids: substances that act on the cannabinoid receptor on our cells

US slang: “pot” from potiguaya, “weed,” “grass,” “herb,” “smoke”, “ganja” and “dope”

Mexico: “mota”, “pasto” and “gallo”

Argentina: “chala”, Venezuela: “hierba”

Ecuador “tobareto” and “grifa”

Spain: “Maria”, France: “Marie Jeanne”

Endogenous Cannabinoids aka Endocannabinoids (eCBs)

• We make them in our bodies ourselves

• Discovered much later than plant sources

• Lipid (fat)-based, released by the postsynaptic membranes in response to neuronal activity

• Arachidonic acid derivatives produced by neurons and glia, the main 2 are:• 2-Arachidonoylglycerol (2-AG)• N-arachidonoylethanolamide/Anandamide (AEA)

Wilson and Nicoll 2002, Science

Endocannabinoid System: CB1

DiMarzo, 2004

ExcitatoryGlutamatergic Synapse

InhibitoryGABA-ergic Neuron

Synaptic activity

CB1-Recepetor Gene ExpressionMouse Brain

: Activity-dependent activation ofVGCC (increase [Ca2+]i) or mGluR1

Allen Brain Atlases

Exogenous Cannabinoids

CBD = CannabidiolNot psychoactiveVery slight CB1/CB2 indirect antagonistOpposes some CNS effects of THCAntagonist at GPR55 receptor? CBD receptor

THC =Δ9 Tetrahydrocannabinol

Psychoactive/euphoria

CB1 receptor agonist(activator)

Cannabis Species

Cannabis sativa – oldest known species used by

humans (China)

Cannabis indica: reference in Ancient Vedas text in India, ~ 1700 bce

Sativa vs. IndicaBoth species: • 80 terpeno-phenol compounds, “cannabinoids”

• THC and CBD are the 2 main compounds

• >420 compounds: e.g. Eugenol: acts at GABAAreceptors

•Sativa more psychic and stimulatory, sometimes anxiety producing, due to higher THC:CBD ratio •Indica strains have more sedative properties, ‘mellow high’, heavy feeling•Many hybrids with various mixtures of THC:CBD and the other cannabinoids give various effects

Hemp

• Technically Cannabis Sativa• But looks very different, tall and

thin; minimal THC (<0.3%), but also not that much total CBD

Hemp/Cannabis in History

• Cannabis sativa – ? ~8,000 bce in China - rope

• Cultivated, used for garments, bowstrings, paper and medicine in China

• 2700 bce – cannabis for menstruation, gout, rheumatism, malaria, constipation, and absentmindedness (Abel, 1980)

• 1st Century AD in China > 100 ailments

• Medicinal use in ancient Egypt, India, Africa, Greece, Rome and Arab world

Cannabis in the 1800’s

• US Dispensary (1854): neuralgia, depression, hemorrhage, pain and muscle spasm

• Ohio Medical Society Committee on Cannabis Indica (1860): efficacy for neuralgic pain, dysmenorrhea, hysteria, delirium tremens, mania, palsy, whooping cough, infantile convulsions, asthma, nervous rheumatism, chronic bronchitis, spasms, tetanus, epilepsy and appetite stimulation.

Cannabinoids: Animal Models

Compound Species

Number of discrete

conditions/models/designs

DoseAnti-

convulsantNo

effectPromotesSeizures

THC 6 310.25-200

mg/kg61% 29% 10%*

CBD 2 211-400 mg/kg

81% 19% 0%

Other plant cannabinoids

2 7 N/A 100% 0% 0%

CB1 receptor agonists

2 55 N/A 73% 18%2%

(7% mixed effect)

Whalley, 2014 American Herbal Pharmacopoeia

Animal models:Cannabidiol (CBD)

has anti-seizure effects

Most notably, in these studies and others, CBD acts independently of

CB1 receptors in the CNS (unlike endocannabinoids and THC)

Hill et al 2013, Brit J of Pharm

Human Data: Anecdotal

• Davis & Ramsay (1949) – THC for 5 institutionalized children who failed PB & PHT -1 seizure free, 1 almost seizure free; 3 no change

• Consroe et al (1975) - young man with epilepsy on PB & PHT. Marijuana led to seizure freedom added to AEDs, but not alone

• Case reports of marijuana reducing seizure activity, (Mortati et al, 2007) provoking seizures,(Tilleli, 2006), or withdrawal causing a seizure (Hedge et al, 2012)

Survey: Marijuana for Epilepsy

• Tertiary care center: 136 adult patients• 48% lifetime use

• 21% active users, 15% in last month

(Gross et al, 2004)

Survey: 19 Pediatric Epilepsy Patients on CBD>THC

• 19 children (2-16 years) used a CBD-enriched medical marijuana – group on Facebook

• CBD Dose <0.5 mg/kg/day to 28.6 mg/kg/d

• THC amount reported as 0 to 0.8 mg/kg/d

• Diagnoses: Dravet syndrome (13), Doose syndrome (4), Lennox Gastaut syndrome (1), and idiopathic epilepsy (1).

(Porter & Jacobson, Epilepsy & Behavior, 2013)

Survey: 19 Pediatric Epilepsy Patients on CBD-enriched Cannabis

• 16 (84%) reduction in seizure frequency

• 2 were seizure free

• 8 (42%) >80% reduction in seizures

• 6 had a 25-60% reduction in seizures.

• Extra Benefits: improved alertness, mood, and sleep.

• Side effects: drowsiness and fatigue.

(Porter & Jacobson, Epilepsy & Behavior, 2013)

From GW Pharmaceuticals website

CBD Enriched Marijuana

From GW Pharmaceuticals website

CBD Enriched Marijuana

Surveys biased

• People who do worse will not stay on it, and less likely to report in the survey – skews results to only positive outcomes

• People may actually be doing worse, but have no idea• They actually ‘feel great’?

• Just as investigators who want their study to succeed may be biased, parents scoring of seizure frequency and severity may slightly be altered

Four Clinical CBD Trials in Epilepsy

STUDY INCLUSION CRITERIANotes

PT # DOSETIME

EFFICACY SAFETY

Mechoulam (1978)

TLE/TREGroups not matched; ? AEDs, no stats

N=95 CBD5 PLA

200/d x 3 mos 4 Rx’d: 2 Sz free, 1 better, 1 unchanged5 Placebo: unchanged

No adverse events

Cunha (1980)

TLE/TRE >= 1 TCSz/wkDB?

N=157 CBD8 PLA

200-300 mg/d3-18 wks

4 CBD seizure free; 1 control seizure free

Seizure-free:1 placebo4 CBD

Ames (1985)

Residential/MR/TRE-baseline data

N=12? CBD v PLA

200 mg/d x 4wks

No group differences Mild drowsiness

Trembly (1990)

TRE adultsConflict of 90 paper and 92 chapter

N=12 ?CBD v PLA

PLAC x 6 mos, CBD 300/dy x 6 mos

No group diff on seizures or cognitive-behavior tasks

No data

Epidiolex (98% CBD) Studies

• Open-label study of children and young adults with TRE – Dravet, LGS, Focal epilepsy, CDKL4, etc

• 6 sites each to enroll 25 children/site (NYU, UCSF, Lurie Children’s, MGH, CHOP, Great Ormond St)

• NYU enrolled 25, added another 35

• Orphan drug indication approved by FDA for Dravet and LGS – plans for RCT

Preliminary Results

Total of 151 patients enrolled, from 3 sitesData on 58 patients, completed 12 weeks• Average age = 11• Average AEDs = 3• Dravet = 12• Drop seizures = 12

• 10 patients completed 20 weeks• 40 patients completed 16 weeks

58 patients through 12 weeks40 patients through 16 weeks

Dravet patients = 12

Drop seizures = 12LGS 4

Epidiolex: Safety

Retention: 95% of patient remain in study

Common adverse events (occurring in 10% or more patients and resulting from all causes):

• Somnolence - 19% of patients

• Fatigue - 11% of patients

Epidiolex: Adverse Events

• 2 withdrawals from treatment: adverse events

• 4 withdrawals from treatment: lack of clinical effect

• Serious adverse events: in 26 patients• 2 deaths: one from SUDEP, one from respiratory

failure due to aspiration

Open-label studies

• Potential Bias

• Both the patient/caregiver/seizure counter, and the investigator are invested in the product working

• Subconscious bias

• Highlights the need for placebo controlled studies

Phase 3 RCTs

Charlotte’s Web vs CBD

Low THC strains

CBD to THC ratio

20 to 1

RoC: Over 450 patients

Colorado, California

Florida

High-CBD Oil Legalities

• Alabama• Kentucky• Wisconsin• Mississippi• Tennessee• Georgia• South Carolina• Iowa• Florida• North Carolina• Missouri• New YorkPrimarily passed with restrictions limited to use in studies

http://www.mpp.org/states/

Regulate Marijuana like alcohol

Dependence

• Cannabis = risk of addiction• rate estimated at 10% of users (Wagner&Anthony

2002, Winstock 2010)

• CB1-activity = addiction

• CB1-blockers = reduce dependence?

CBD: preliminary evidence shows ANTI-addiction properties

Wolff V et al. Cannabis use, ischemic stroke, and multifocal intracranial vasoconstriction: a prospective study in 48 consecutive young patients. Stroke. 2011 Jun;42(6):1778-80.

Multifocal intracranial stenosis associated with cannabis use: 21% (10/48)

Renard D, Taieb G, Gras-Combe G, Labauge P.J Stroke Cerebrovasc Dis. 2012 Jan;21(1):82-3

Psychiatric side-effects

Approved Pharmaceuticals

• Cesamet – antinausea

• nabilone

• Marinol – antinausea

• synthetic dronabinol (THC); Schedule III

• Dizziness 50%, hallucination 6%, paranoia 5%

• Sativex (Canada) – cancer pain, spasms/spasticity in multiple sclerosis

• 100 µl = 2.7mg THC, 2.5mg CBD

Pertwee RG ed: Handbook of Cannabis, Oxford University Press, 2014.

Sleep

Pertwee RG ed: Handbook of Cannabis, Oxford University Press, 2014.

Science Summary

• CB1 receptors: in Brain

• CB2 receptors: in Immune system

• THC: activates CB1• May improve or worsen seizures, per evidence

• more psychic and anxiety side-effects

• the net effect on different regions of different brains is unique and not predictable

• CBD: not active at CB1• Evidence exists only for anti-seizure properties

• with less psychic changes, may have anti-addiction properties

High-CBD Summary

• Different strains of cannabis:• different levels and proportions of THC & CBD

• Charlotte’s web – high CBD

• Risks of Cannabis: stroke? heart attack? • Need to be studied more formally in our specific

target population

• Drug-CBD interactions exist

• Problem: most can’t wait for the research

• We will have studies on Epidiolex 98% CBD in the upcoming years

Cannabinoids:Miraculous

Claims; Not all tested… yet

http://idrasilrx.com/doctor-information/human-receptor-information/