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

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

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. 

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

Binding Affinities of Endogenous and Exogenous Cannabinoids Ki @ CB1R Ki @ CB2R CBD 4350 - >10,000 nM 2400 - >10,000 nM Δ9-THC 5 - 80 nM 3 - 75 nM Higher number means it takes more of the compound to bind. Pharm. Rev. (2010) 62(4): 588-631

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

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.

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*

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.

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

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 ± 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-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

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

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.

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.

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.

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 Email: sweta@Stanford.edu 650-721-1458 Additional contact: prevent@uabmc.edu Regina Ryan PREVeNT Program Manager 205-975-2890 IRB# F160509001