MEDICAL CANNABIS RELATED THERAPEUTICS FOR THE SYMPTOMATIC TREATMENT OF EPILEPSY
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MEDICAL CANNABIS RELATED THERAPEUTICS FOR THE
SYMPTOMATIC TREATMENT OF EPILEPSY
MISTY D. SMITH, PH.D.1,2
1DEPARTMENT OF PHARMACOLOGY & TOXICOLOGY, COLLEGE OF PHARMACY
2ORAL BIOLOGY, MEDICINE & PATHOLOGY SECTION, SCHOOL OF DENTISTRY,
UNIVERSITY OF UTAH
10 Aug 2021 Utah Cannabinoid Product Board Meeting ©UNIVERSITY OF UTAH HEALTH, 2017
THE UNMET NEED FOR EPILEPSY THERAPEUTICS
• Epilepsy affects ~2.9 million people in USA & over 65 million people worldwide.
https://quotesgram.com/img/epilepsy-awareness-quotes/738382/
• Characterized by recurrent seizures, epilepsy encompasses a spectrum of
different disorders caused by a variety of etiologies.
• Adversely impacts the patient’s quality of life.
• Prevalence of medically refractory epilepsy in the US is >730,000 people and
21.7 million people worldwide
SOURCE: www. cdc.gov/epilepsy; Fisher RS, et al. (2005); Kwan and Brody (2000); IOM report on epilepsy (2012)
10 Aug 2021 Utah Cannabinoid Product Board Meeting ©UNIVERSITY OF UTAH HEALTH, 2017
THE UNMET NEED FOR EPILEPSY THERAPEUTICS
• None of currently available antiseizure drugs (ASDs) prevent the underlying
cause of epilepsy or the epileptogenic process.
• 1/3rd of patients with epilepsy fail to achieve seizure freedom after two or more
appropriately selected & dosed ASDs
• Patients resistant to multiple ASDs have an increased risk of sudden
unexpected death in epilepsy (SUDEP) and other forms of epilepsy-related
mortality.
SOURCES: Nilsson L et al. ((1999); Kwan and Brody (2000); Walczack TS et al. (2001); Kwan P. et al. (2011)
10 Aug 2021 Utah Cannabinoid Product Board Meeting ©UNIVERSITY OF UTAH HEALTH, 2017
RARE PEDIATRIC EPILEPTIC ENCEPHALOPATHIES
• Dravet syndrome: rare form of intractable epilepsy • Lennox-Gastaut syndrome (LGS): rare form of
that begins in infancy and accumulates morbidity intractable epilepsy involving with multiple
throughout lifetime. different seizure phenotypes,
• Incidence of 1:15,700 individuals, 80% have a particularly tonic (stiffening) and atonic (drop)
mutation in their SCN1A gene. seizures.
• Behavioral & developmental delays, movement & • Intellectual development is usually delayed and
balance issues and disruptions of autonomic nervous often worsens over time. Behavioral problems,
system (difficulty regulating body temperature, heart including hyperactivity, agitation, aggression and
rate, blood pressure) require lifetime care. autism, are common.
• Severely impacts both the patient’s and the family’s • Although LGS may be caused by early brain injury
quality of life. from infection or trauma, genetic causes, or brain
malformations, in 1 out of 4 children the cause of
• 15-20% mortality rate due to SUDEP (Sudden
Unexpected Death in Epilepsy), prolonged seizures or LGS is unknown.
seizure-related accidents (i.e., drowning & infections). • Severely impacts both the patient’s and the
• Current treatment options are limited family’s quality of life.
• Current treatment options are limited
SOURCE: Wu, E., et. al. (2015); Cooper, M.S., et. al. (2016); Skluzacek, et. al. (2011).
©UNIVERSITY OF UTAH HEALTH, 2017
LONG HISTORY OF MEDICINAL CANNABIS:
Early-Mid 20th Century
2900 B.C. 1000 B.C. 1841 1850-1942- Cannabis listed in US
Pharmacopiea
1906 – Pure Food & Drug Act (labels
patent medicines).
1937 – Marijuana Tax Act regulated
import, cultivation, possession &
distribution of cannabis (officially
illegal)
1938 – Food, Drug & Cosmetics Act
gave federal oversight
1970 – Controlled Substance Act
Present Day
Epidiolex™ FDA approvals for 2013 - Weed© CNN docuseries hosted
seizures in rare pediatric epilepsy by Sanjay Gupta on Charlotte Figi, 6 y.o.
syndromes: patient w/ Dravet Syndrome on CBD oil
• June 2018 – Dravet & Lennox
Gestaut Syndrome
• July 2020 – Tuberous Sclerosis
Syndrome
SOURCES: Time’s Documentary “A Journey for Oil”; Spicer 2002
10 Aug 2021 Utah Cannabinoid Product Board Meeting ©UNIVERSITY OF UTAH HEALTH, 2017
PHYTOCANNABINOIDS:
– The cannabis plant produces between 80-100 cannabinoids plus > 300 non-cannabinoid chemicals.
– Subdivided based on chemical structure and extent of psychological activity:
• Cannabigerols (CBG)
• Cannabichromenes (CBC)
• Cannabidiols (CBD)
• Cannabidivarin (CBDV)
• Tetrahydrocannabinols (THC)
• Cannabinol (CBN) & cannabinodiol (CBDL)
• Other cannabinoids:
– cannabicyclol (CBL), cannabielsoin (CBE), cannabitriol (CBT) and others
– Two most prevalent phytocannabinoids in the marijuana plant: D9-THC and CBD.
– Most exogenous cannabinoids target endogenous cannabinoid receptors (CB1 & CB2) and have either
orthosteric or allosteric effects.
SOURCE: http://LearnAboutMarijuanaWA.org/factsheets/cannabinoids.htm
10 Aug 2021 Utah Cannabinoid Product Board Meeting ©UNIVERSITY OF UTAH HEALTH, 2017
TAKE HOME (PRIOR TO 2015)
• Despite anecdotal reports & widespread interest from
parents, patients, and the scientific community regarding
the potential of medical cannabis to treat seizures, a
systematic analysis of clinical trial data (1978-2014) by the
Academy of Neurology and a Cochrane Database
review both concluded that “medical cannabis is of
“unknown efficacy” to treat epilepsy.”
SOURCES: Koppel BS, et al. (2014); Gloss D and Vickrey B ( 2014)
10 Aug 2021 Utah Cannabinoid Product Board Meeting ©UNIVERSITY OF UTAH HEALTH, 2017
INADEQUATE CLINICAL TRIAL DATA (1978-2014)
• Double blinded clinical trial in 9 patients with treatment resistant epilepsy. Of the 4 patients receiving
200 mg CBD daily for 3 months. 2 patients were seizure free during treatment, one patient had partial
improvement, the other had no improvement. No significant toxicity was reported. (Mechoulam R,
Carlini EA (1978))
• Double blinded clinical trial in 15 patients (ages 14-49 yrs) with secondarily generalized epilepsy with
temporal focus. Of the 8 patients were randomly assigned to the treatment group (200-300 mg CBD
daily for 8-18 weeks) in addition to their standard ASD regiment, 4 patients were reported as “almost
free of convulsive crisis”, 3 had partial improvement and one had no change. No toxicity was reported.
(Cunha JM, Carlini EA, Pereira AE, et al. (1980))
• Double blinded clinical trial by Ames et al. (1986) in 12 patients institutionalized due to “mental
retardations with uncontrolled seizures.” In the 6 patients receiving CBD treatment (300 mg of CBD daily
for one week and then 200 mg daily for three weeks) or the control groups, no difference in seizure
frequency was reported. Mild drowsiness was only reported adverse affect. (Ames FR, Cridland S
(1986))
• Cross-over clinical trial by Trembly et al. conducted in 12 patients in which all were treated with
placebo for 6 months followed by 300 mg of CBD or placebo in a crossover design over the next 12
months, No change in seizure frequency or adverse effects were reported. (See Gloss D, Vickrey B.
(2014))
SOURCES: In addition to the articles cited above, Zaheer et al. (2018); Gloss & Vickrey (2014), Minnesota Dept. of Health
Office of Medical Cannabis report on “Review of Medical cannabis Studies for Qualifying Medical Conditions” July 2016
©UNIVERSITY OF UTAH HEALTH, 2017
CANNABIDIOL (EPIDIOLEX™)
• First FDA approved Cannabis-derived treatment for seizures associated with rare,
treatment-resistant pediatric epilepsy syndromes
• Proprietary oral solution of purified plant-derived cannabidiol, or CBD, in oil.
• Indications:
– Treatment of seizures associated with Dravet’s & Lennox-Gestaut Syndromes in patients 2 years and
older. (FDA approved in June 2018)
– Treatment of seizures associated with Tuberous Sclerosis Complex (TSC) in patients one year of age and
older. (FDA approval in 2020)
– Well-tolerated in doses up to 25mg/kg/d
• Rescheduled to Schedule V since Oct 2018
• Most Common Side Effects: sleepiness, decreased appetite, diarrhea, transaminase
elevation
SOURCE: https://www.gwpharm.com/healthcare-professionals/research-trials/epilepsy
2019 Addictions Update Conference: Science, Policy and Treatment ©UNIVERSITY OF UTAH HEALTH, 2017
EPIDIOLEX™ CLINICAL TRIALS (GW PHARMACEUTICALS)
Randomised, double-blind, placebo-controlled trials (since June 2015): patients
reported significant improvement (% symptom reduction).
SOURCE: GW Biosciences (2018); Thiele et al. (2018); Guy et al (2014); Devinsky et al. (2015)
10 Aug 2021 Utah Cannabinoid Product Board Meeting ©UNIVERSITY OF UTAH HEALTH, 2017EPIDIOLEX™ TRIALS (GW PHARMACEUTICALS)
SOURCE: https://www.epidiolexhcp.com/efficacy-and-safety/LGS; https://www.epidiolexhcp.com/efficacy-and-safety/dravet-syndrome
10 Aug 2021 Utah Cannabinoid Product Board Meeting ©UNIVERSITY OF UTAH HEALTH, 2017TUBEROSCLEROSIS COMPLEX (TSC)-ASSOCIATED SEIZURES
a new indication for Epidiolex™ (GW Pharmaceuticals) for the treatment of seizures
associated with TSC was FDA approved in 2020.
SOURCE: https://www.epidiolexhcp.com/efficacy-and-safety/tsc
10 Aug 2021 Utah Cannabinoid Product Board Meeting ©UNIVERSITY OF UTAH HEALTH, 2017INSYS THERAPEUTICS INC. (PHOENIX, AZ)
• Synthetic CBD oral solution (up to 40
mg/kg/day)
• Orphan drug designation granted in June
2014 for the treatment of Lennox-Gestaut
syndrome and for the treatment of infantile
spasms in August 2015.
SOURCE: INSYS Therapeutics, 2016; Parikk, 2018
10 Aug 2021 Utah Cannabinoid Product Board Meeting ©UNIVERSITY OF UTAH HEALTH, 2017POTENTIAL CONTRIBUTING MECHANISMS (CB-RECEPTOR INDEPENDENT)
• Anticonvulsant effects
- inhibition of GPR55 mediated presynaptic calcium release,
- modulation of adenosine signaling (also anti-inflammatory)
• Anti-inflammatory, antioxidant, & neuroprotective effects:
- reduction in serum cytokine levels
- (i.e., IL-4, IL-5, IL-13, IL-6, and TNF-α).
• Other biological effects:
- Serotonin (5HT1A) agonist (antidepressant)
- CBD acts as a potent FAAH enzyme inhibitor, which increases endogenous anandamide levels
- Antiemetic,
- Anxiolytic effects
TAKE HOME: More research is needed!
– Mechanisms underlying CBD’s therapeutic effects remain unclear
– Much More to Learn: Drug interactions, Long Term QOL Outcomes, Special Populations
SOURCE: Consroe et al., 1986; During & Spencer, 1992; Mechoulam et al., 2002; Grotenhermen, 2004; Vaccani et al., 2005; Sylantyev et al., 2013; Rimmerman et
al., 2013; Ianotti et a., 2014; Devinsky et al., 2014.
2019 Addictions Update Conference: Science, Policy and Treatment ©UNIVERSITY OF UTAH HEALTH, 2017WHAT ABOUT THC?
• No clinical trial data available for THC,
THC:CBD combinations, other cannabinoids or
medical cannabis in patients with epilepsy
SOURCE: www.clinicaltrials.gov
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