Brenda Porter, MD, PhD speaks about cannabadiol and medical marijuana for the treatment of epilepsy and Lennox-Gastaut Syndrome

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

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

3. The two most commonly discussed chemicals in
marijuana
THC
(delta-9-tetrahydro-
cannabinol)
CBD
(cannabidiol)
Psychoactive √
Anti-emetic √
Appetite stimulant √
Analgesic √ √
Anti-inflammatory √
Anti-seizure √
Anti-spasmodic √
Neuroprotective √

4. Binding Affinities of Endogenous and
Exogenous Cannabinoids
Ki @ CB1R Ki @ CB2R
2-AG 58 - 472 nM 145 - 1400 nM
Anandamide 61 - 543 nM 279 - 1940 nM
CBD 4350 - >10,000 nM 2400 - >10,000 nM
Δ9-THC 5 - 80 nM 3 - 75 nM
Pharm. Rev. (2010) 62(4): 588-631

5. 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.

6. Poorly Controlled Studies
• Small studies, 1940-1990 ~ 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.
36.5% median reduction in weekly convulsive
seizures. Somnolence diarrhea , decreased
appetite, fatigue, convulsion, status epilepticus
were side effects noted. 2016 Devinsky et al.

7. 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*

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

11. 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)
1.AED levels that changed.
Clobazam
a
27 264.7 ± 136.3 331.1 ± 143.2
(dose unchanged)
310.9 ± 104.2
(dose unchanged)
30–300 ng/ml
430.3 ± 327.6
(dose decreased)
285.0 ± 176.0
(dose decreased)
N-
desmethylclobaza
m
a
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)
Eslicarbazepine
a
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 14 24.8 ± 12.8 25.6 ± 13.6 27.0 ± 14.7 (dose
unchanged)
5–5

12. 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

13. Medical Marijuana
• 10 kg child to be on 50-100mg 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 15-30
dollars per day. Or 500-1000 dollars a month.

14. 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.

15. Predictions
• There will be a clinical formulation of CBD
available in the next 1-2 years for epilepsy.
• 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.

16. NIHTSCClinicalTrial–PREVENTING EPILEPSY USING
VIGABATRIN IN INFANTS WITH TUBEROUS SCLEROSIS
COMPLEX (PREVeNTTrial)
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
Email: sweta@Stanford.edu
650-721-1458
Additional contact:
prevent@uabmc.edu
Regina Ryan PREVeNT Program Manager
205-975-2890
IRB# F160509001