Fawad Khan, MDEpileptologist - The International Center for Epilepsy at Ochsner,

Ochsner Neuroscience Institute

2019 Ochsner Regional Neurosciences Symposium

Conflict of Interest

• None

• Commercially available products will be mentioned

• Pharmaceutical companies and their products will be mentioned

The plant

• Cannabis is derived from the plant Cannabis sativa, Cannabis indica, or Cannabis ruderalis

• The cannabis plant contains cannabinoids

7 cannabigerols 3 cannabicyclols

5 cannabichromenes 5 cannabielsoins

7 cannabidiols (CBD) 7 cannabinols

9-Δ-9-tetrahydrocannabidiols(THC-9)

2 cannabinodiols

2-Δ-8-tetrahydrocannabidiols(THC-8)

9 cannabitriols

History

History

• More than 500 compounds have been identified, >100 cannabinoids and several other chemical classes

• 19th century - Cannabinol (CBN) was the first phytocannabinoid to be extracted

• 1940 - Cannabidiol (CBD)

• 1942 - Delta-9-tetrahydrocannabinol (THC)

• 1964 - THC was isolated (marijuana's psychotropic properties)

Forms• Synthetic cannabinoids:

• 2 FDA-approved prescription cannabinoids 1. dronabinol (Marinol)2. nabilone (Cesamet)

• Natural:

• FDA approved Epidiolex is an oil-based product with >98% CBD and <3% THC

• Realm Oil is an extract of a strain of medical marijuana with a CBD/THC ratio of 16:1.

• Oro-mucosal spray nabiximols that contain both THC and CBD

• Other forms

1840 - cannabis was used for babies with infantile convulsions, patients with epilepsy, spasticity, and arthritis.

https://medium.com/@dubhempmuseum/sir-william-brooke-oshaughnessy-medical-cannabis-pioneer-c94798fd7722

THC

THC

➢Agonist - cannabinoid 1 (CB1) receptors - highly expressed in the hippocampus, amygdala, cingulate, cerebral cortex, basal ganglia, midbrain, and medulla.

➢Transmembrane G protein coupled receptor - neuronal inhibition by decreasing calcium influx and increasing potassium efflux across the cell membrane.

➢CB1 – both inhibitory (GABAergic) and excitatory (glutamatergic) neurons.

➢Partial agonist - CB2 receptors- immune and hematopoietic cells• Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-

tetrahydrocannabivarin. Br J Pharmacol. 2008;153: 199-215.

CBD

CBD

➢Agonist at the 5-HT1a, alpha 3 and 1 glycine receptors

➢Binds very weakly to CB1 receptors, diminishes the effects of CB1 activation

➢CBD is highly lipophilic, allowing access to intracellular sites of action, modulates intracellular calcium.

➢CBD actions on calcium homeostasis in hippocampal neurons may provide a basis for CBD neuroprotective properties

• Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153: 199-215.

Receptors and role in Epilepsy

• Activation of CB1 receptors by THC inhibit synaptic transmission -modulate epileptiform and seizure activity

• CB1 receptors are expressed on many glutamatergic synapses that have been implicated in seizure threshold modulation. CBD may act at CB1 receptors to inhibit glutamate release

AAN published a position statement (2014)

➢‘probably effective’ for some symptoms of multiple sclerosis, including spasticity, central pain, spasms, and urinary dysfunction

➢‘probably ineffective’ for levodopa-induced dyskinesia of Parkinson’s disease

➢‘unknown efficacy’ in nonchorea symptoms of Huntington’s disease, Tourette’s syndrome, cervical dystonia, and epilepsy

AES position statement (2014)

1) Positive effects of the CBD are from anecdotal reports only with robust scientific evidence lacking to establish medical marijuana as a safe and effective treatment of epilepsy

2) Potential negative effects on learning, memory, and behavior

3) Should be studied using well founded research methods

4) Status as a Schedule 1 substance should be reviewed

5) The risk/benefit ratio does not currently support the use of marijuana for treatment of seizures at this time

Medical Marijuana - Safety

CVS & Resp

• CVS Acute: Tachycardia, increased cardiac labor, systemic vasodilation, and increased BP

• Long-term: bradycardia and hypotension

• Resp Acute: Increase inflammation of large airways, increase airway resistance, and destroy lung tissue

• Chronic:Increased risk of chronic bronchitis, increased risk of emphysema, chronic respiratory inflammation, impaired respiratory function

Immune system and sleep

• Immunosuppressive properties - potential biphasic impact on the immune system

• Cancer

• Sleep - Increase total sleep time – insomnia pts, cancer patients with chronic pain, individuals with post-traumatic stress disorder

• Decrease slow wave sleep

Cognition

• Acute

• Impair free recall, acquisition, working memory, and procedural memory

• Impairments are also demonstrated on measures of attention, sensory perception, and executive function

• Impairments in gross and simple motor tasks

• Possible impairment of abstract reasoning and decision making

• Chronic

• Persistent pronounced deficits in visual attention, verbal fluency, inhibition, short-term recall, impulsivity, and executive functioning

Studies on Mental Health

• A retrospective, cohort study of Swedish data on 50,087 individuals regarding self reported use of cannabis and other drugs

• Cannabis was associated with an increased risk of developing schizophrenia in a dose-dependent fashion

• Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ. 2002;325:1199.

• Lancet Review (35 studies) showed increased risk of any psychotic outcome in individuals who had ever used cannabis with evidence of a dose response effect, and greater risk in people who used cannabis most frequently

• Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;37 0:319-328.

• JAMA Meta-analyses show that adults who are heavy cannabis users exhibit significant deficits in learning, working memory, and attention

• Volkow ND, Swanson JM, Evins AE, et al. Effects of cannabis use on human behavior, including cognition, motivation, and psychosis: a review. JAMA Psychiatry. 2016;73:292-297.

• Birth cohort of 1037 individuals

• Cannabis use was ascertained at ages 18, 21, 26, 32, and 38 years

• Cognitive impairment was mainly associated with cannabis use from adolescence, and more persistent use led to greater declines in cognitive function

• Cessation of cannabis use did not fully restore neuropsychologic function in adolescent-onset cannabis users

• Meier MH, Caspi A, Ambler A, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012;109:E2657-E2664.

Structural Effects on Nervous System

• Cannabis-mediated neurodegeneration - white matter in the frontal lobes, fornix, fimbria of the hippocampus, frontal-limbic connections, corpus callosum, and commissural fibers

• Cerebellar white matter atrophy

• Axonal radiculopathy

• Impaired axonal connectivity in hippocampus, splenium of the corpus callosum, and commissural fibers

• Mandelbaum, David E., and M. Suzanne. "Adverse structural and functional effects of marijuana on the brain: evidence reviewed." Pediatric neurology 66 (2017): 12-20.

Pregnancy & children

• Birth defects, low birth eight, and an increased risk of childhood cancer, poor neurodevelopmental outcomes, aggressive behavior and attention problems in girls

• Babies - show traits indicative of neurological development problems

• Children - decreased problem-solving skills, poor memory and attention

Public health concern

• Cannabinoid content and consequent potency has shown extreme variance depending on the light, temperature, humidity, and soil type during cultivation, as well as genetic factors

• Method of administration (e.g., oral, smoked, vaporized) and form of cannabinoid consumed (e.g., stems and buds, hashish, hash oil, extract, synthetic) can impact the bioavailability

2016

• 84 products were purchased and analyzed (from 31 companies).

• Only 26 had accurate CBD content labeling

• THC was detected in 18 of the products

• JAMA. 2017;318(17):1708-1709.

• 94 people have presented to ER (89 in Illinois, 2 in Indiana, 1 in Maryland, 1 in Missouri, and 1 in Wisconsin) with serious unexplained bleeding.

• Long-acting vitamin K-dependent antagonist toxicity.

• Do you ship to all 50 States?

• Yes. CW™ Hemp proudly ships our Charlotte’s Web™ proprietary hemp extracts to all 50 States. The United States Farm Bill of 2014 classified industrial hemp as containing less than 0.3% THC on a dry-weight basis. Because Charlotte’s Web™ products contain less than 0.3% THC, we are allowed by U.S. Federal law to conveniently ship to your doorstep.

Evidence in Epilepsy

Summary of evidence

• 1970 – 2016• Several animal studies on electrical convulsant and chemoconvulsant models.

• Several small series

• 1 pilot study of CBD versus placebo

• 2 papers on parental surveys of the effect of non-purified preparations of cannabis-based products for pediatric epilepsy.

• Cochrane review

• 2016• CBD (Epidiolex®)

Cochrane systematic review (2012)

• 4 randomized controlled studies

• Subjects 48

• Design flaws, including incomplete baseline quantification of baseline seizure frequency, indeterminate time periods for outcome determination, inadequate (or missing) statistical analysis, a lack of sufficient detail to adequately evaluate

• Based on the low quality of the reports available, there is insufficient data available to draw any conclusions regarding the efficacy and or long-term safety of CBD in treating epilepsy

Cannabis, Cannabidiol, and Epilepsy - OCTOBER 2018 PRACTICAL NEUROLOGY 35

Long term safety - CBD (Epidiolex®)

• 607 patients at 25 centers; Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks.

• 88% experienced some sort of side effect

• Severe side effects were reported in 33% of patients,

• convulsion (9%),

• status epilepticus (7%)

• pneumonia (5%)

• vomiting (3%)

• Milder side effects included somnolence, fatigue, diarrhea, and reduced appetite• Szaflarski, Jerzy P., et al. "Long‐term safety and treatment effects of cannabidiol in children and adults with

treatment‐resistant epilepsies: Expanded access program results." Epilepsia 59.8 (2018): 1540-1548.

Analysis of the open label extension of two phase 3 RCT: GWPCARE3 and GWPCARE4

Analysis of the open-label extension of two Phase 3, RCT: GWPCARE1 and GWPCARE2

11% discontinued due to AE 7% discontinued due to AE

diarrhea, convulsion, somnolence, pyrexia, vomiting and decreased appetite

13% - elevations in liver transaminases >3× upper limit of nml

9 % - Elevated liver transaminases >3×upper limit of nml

5 deaths; none related 2 deaths; none related

48–70% reduction in drop sz48–63% reduction in total sz

44%-57% for convulsive sz49%–67% for total sz

Hepatotoxicity with CBD products

• Many antiepileptic drugs carry some risk of hepatotoxicity

• Discontinuation if LFT levels rise to 3X the ULN and bilirubin levels are 2X the ULN

• Elevation of LFTs appears to be most common in the first 2 months of treatment but has also been observed in later stages of treatment.

• Hepatotoxicity risk of pharmaceutical-grade CBD appears to be more common if there is polypharmacy with valproic acid or clobazam

• Liver monitoring is recommended at months 1, 3, and 6 after initiating treatment or monthly after dose changes or addition of another AED that interacts with CBD

Drug interaction with AEDs

• Topiramate and rufinamide both appear to have dose-related increases in serum concentrations in the presence of CBD

• Serum increases of zonisamide and eslicarbazepine were present to a lesser extent

• Strong CYP3A4 or CYP2C19 inhibitors and inducers appear to increase and decrease CBD serum concentrations, respectively

• N-desmethylclobazam concentrations increased by 60% compared to pre-Epidiolex concentrations

• Geff rey AL, Pollack SF, Bruno PL, Thiele EA. Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia 2015; 56: 1246–51.

• 24 days

• 16 subjects

• No notable effects on the PK of the sensitive CYP3A4 substrate midazolam

1. Combination of CBD with CLB resulted in a bidirectional DDI that increased levels of active metabolites of both 2. No evidence of DDI between CBD and VPA3. No effect of CBD on CYP3A4 activity (MDZ)4. The slight increase of exposure to STP when coadministered with CBD is not expected to result in a clinically important

DDI.

Legality and Cost

31 states, the District of Columbia, Guam, and Puerto Rico have legalized marijuana for medical use

State law is more stringent than federal law

• There is no lawful possession of a substance listed in Schedule I, except for the marijuana products authorized in the state medical marijuana program

• CBD is a compound of marijuana and therefore is considered marijuana under Louisiana law.

• Violations of the Louisiana Revised Statutes or Louisiana Administrative Code can subject a person to criminal and/or administrative action

Medical marijuana grown at the LSU AgCenter in Baton Rouge (Photo by Hampton Gruenwald) (Nola.com)

LA medical marijuana program “regulatory hurdles & testing requirements”

• January 2019 (Nola.com)

• Only one of the two growth facilities is open for operation—the LSU Agricultural Center’s plant run by GB Sciences Louisiana. Southern University AgCenter and its partner, changed ownership to the Pennsylvania-based company Ilera Holistic Healthcare

• The Louisiana Department of Agriculture and Forestry (LDAF), which acts as a regulator for the program in Louisiana, had filed a request for proposal seeking an independent lab in September, they elected not to go with any of the three labs that applied to do the work. They then chose to do the testing.

• Physicians will not issue a prescription but a "physician recommendation form" because federal law still prohibits prescribing.

What’s new?

• ZYN002, an investigational transdermal cannabidiol (CBD) gel

• The phase 2A, randomized, double-blind, placebo-controlled study

• N=174

• 12-week study - 24-month open-label extension

• 95 discontinued the study??

• N=63, seizure rates were -49%, -53%, -55%, -52%, -54%, and -55% for Months 3, 6, 9, 12, 15, and 18, respectively

• Serious adverse events - seizures (n=2), increased anxiety (n=1); one death was reported after the Month 15 visit.

• O'Brien T, Berkovic SF, French J, et al. Synthetic Transdermal Cannabidiol for the Treatment of Focal Epilepsy in Adults. Presented at: 72nd Annu al Meeting of the American Epilepsy Society; November 30-December 4, 2018; New Orleans, LA. Poster 2.253.

• To enroll 28 children from four Canadian cities• Oil-based extract of Cannabis sativa purchased from CanniMed®

Therapeutics Incorporated (Saskatoon, Canada) named ‘CanniMed® Oil 1:20’ with 1 mg/mL of Δ9-THC and 20 mg/mL of CBD

The Future awaits…

• Other components of cannabis may have anticonvulsant properties (eg, d-9-tetrahydrocannabivarin [THCV], cannabidivarin [CBDV], d-8-tetrahydrocannabinol [d-8-THC], and cannabinol [CBN]

• dos Santos RG, Hallak EC, Leite JP, Zuardi AW, Crippa JAS. Phytocannabinoids and epilepsy. J Cli Phar Ther. 2015; 40:135-143.

Thank you