1. Update on Marijuana for the Treatment of Epilepsy
Brenda Porter MD, PhD

2. Cannabis: A complex mixture of chemicals
~480 pharmacologic entities
Cannabinoids
(~66-100)
Non-cannabinoid psychoactive components
(~20-40+)
Other
(hundreds)

3. Disclosures
Dr. Porter has received compensation for working on an advisory board for Upsher-Smith, a data safety monitoring board for a clinical trial run by Greenwich Biosciences, and has through marriage received stock and compensation from Johnson and Johnson. 

4. The two most commonly discussed chemicals in marijuana
THC
(delta-9-tetrahydro-cannabinol)
CBD
(cannabidiol)
Psychoactive (makes you high) √
Anti Nausea
Appetite stimulant
Pain Relief
Anti-inflammatory
Anti-seizure
NOTE NOT √
Anti-spasmodic
Neuroprotective

5. Binding Affinities of Endogenous and Exogenous Cannabinoids
CB1R
CB2R
CBD
>10,000 nM
>10,000 nM
Δ9-THC nM nM
Higher number means it takes more of the compound to bind.
Pharm. Rev. (2010) 62(4):

6. CBD Mechanism of Action
Classical cannabinoid action UNLIKELY
THC example of leading to more neurotransmitter release
Doesn’t bind with high affinity to CB1R or CB2R
Data on CB1R knockout animals
Other mechanisms of action
Heteromers, or modulatory effect
Other receptors (GPR55 antagonism, TRPV, 5HT1A,
Adenosine reuptake inhibition
Anti-inflammatory
Extrasynaptic GABA receptors.
Increased Serotonin synaptic activity

7. Poorly Controlled Studies
Small studies, ~ ½ showed seizure improvement ½ did not.-No notable side effects.
Open label trial (GW pharma CBD) severe childhood onset epilepsy 12 weeks. 214 children % median reduction in weekly convulsive seizures. Somnolence diarrhea , decreased appetite, fatigue, convulsion, status epilepticus were side effects noted Devinsky et al.

8. Placebo Controlled Trial-Dravet
Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome
Orrin Devinsky, M.D., J. Helen Cross, Ph.D., F.R.C.P.C.H., Linda Laux, M.D., Eric Marsh, M.D., Ian Miller, M.D., Rima Nabbout, M.D., Ingrid E. Scheffer, M.B., B.S., Ph.D., Elizabeth A. Thiele, M.D., Ph.D., and Stephen Wright, M.D., for the Cannabidiol in Dravet Syndrome Study Group*

10. CBD in Dravet, 2017
Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia (fever), somnolence (sleepy), and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.

12. Epidiolex in Lennox-Gastaut Syndrome
170 patients, 10mg/kg/day and 20mg/kg/day
Drop seizures were reduced 37% or 42% respectively
Rare but present withdrawal for adverse events
Drowsiness and Gastrointestinal issues

13. Interactions between cannabidiol and commonly used antiepileptic drugs Authors Tyler E. Gaston,E. Martina Bebin,Gary R. Cutter,Yuliang Liu, Jerzy P. Szaflarski,
AED level N
Mean baseline level
Mean first “on CBD” level
Mean second “on CBD” level
Normal AED level range (trough)
AED levels that changed.
Clobazama 27
264.7 ± 136.3
331.1 ± (dose unchanged)
310.9 ± (dose unchanged)
30–300 ng/ml
430.3 ± (dose decreased)
285.0 ± (dose decreased)
N-desmethylclobazama 26
2,207.5 ± 1,854.0
3,727.7 ± 1,549.3 (dose unchanged)
3,696.8 ± 1,027.1 (dose unchanged)
300–3,000 ng/ml
6,226.8 ± 4,006.9 (dose decreased)
4,843.8 ± 2,982.6 (dose decreased)
Eslicarbazepinea 4
14.4 ± 7.4
16.8 ± 7.9
17.8 ± 9.1
2–28 μg/ml
Topiramate 20
10.3 ± 5.9
10.8 ± 7.0
11.3 ± 8.3
4.5–20 μg/ml
Zonisamide 14
17.2 ± 12.2
19.3 ± 13.0
17.2 ± 9.3 (dose unchanged)
10–40 μg/ml
42.0 (dose decreased in 1 adult)
Rufinamide
24.8 ± 12.8
25.6 ± 13.6
27.0 ± 14.7 (dose unchanged)
5–5

14. Is “medical” marijuana effective?
Small NOT well controlled studies suggest parents report improvement in many often more than half of the children.
Side effects are relatively mild Somnolence, fatigue unsteady.
NOTE often on very low doses of CBD.
Porter et. al. 2013,Press et. al. 2014, Tzardok 2016

16. Medical Marijuana
10 kg child to be on mg twice a day of CBD for the study.
Label and testing of CBD content is NOT regulated.
Most bottles are poorly labeled and you, like I have to guess what you are giving your child.
If bought in bulk the cost would be dollars per day. Or dollars a month.

17. Ongoing Clinical Trials
Trial of CBD are ongoing- At least 19 open trials of CBD in clinicaltrials.gov for epilepsy.
Several are closed and have data but not yet reported.
One trial in ASD in Israelis listed in clinicaltrials.gov.

18. Predictions
There will be a clinical formulation of CBD available in the next few months for epilepsy.
Approved for drop seizures in Dravet and Lennox-Gastaut
There will be more studies of CBD in autism, inflammation, pain.
It will not be a miracle cure for most patients but a few it might be quite helpful for treating epilepsy.

19. NIH TSC Clinical Trial – PREVENTING EPILEPSY USING VIGABATRIN IN INFANTS WITH TUBEROUS SCLEROSIS COMPLEX (PREVeNT Trial)
NEEDED: Newborns to 6 months old infants with TSC with NO history of seizures
What:
The objective of this study is to compare the developmental impact of early versus delayed treatment with vigabatrin.
The results will help determine if treatment with vigabatrin in TSC infants can prevent or lower the risk of developing infantile spasms or refractory seizures.
Who:
Infants up to 6 months old with TSC and no history of seizures may be eligible to
participate.
Compensation:
Compensation may be available to help with study related travel expenses.
Details:
For more information, contact: Stanford Principal Investigator
Sweta Patnaik (Study Coordinator) Brenda Porter, MD
Additional contact:
Regina Ryan PREVeNT Program Manager
IRB# F