Philippe Douyon, MD Epileptologist Northeast Regional Epilepsy Group Marijuana in Epilepsy Philippe Douyon, MD Epileptologist Northeast Regional Epilepsy Group

“when I was mayor of Burlington, in a city with a large population, I can tell you very few people were arrested for smoking marijuana. Our police had more important things to do.” – Bernie Sanders “If your kid was caught selling marijuana or growing enough that it’s a felony conviction, they could be in jail for an extended period of time, they also lose their ability to be employable. So I want to change all of that.” – Rand Paul ‘an interesting national experiment’ that should be allowed to play out further.” – Jim Webb “we can now watch and see what happens in Colorado and Washington State.” – Ted Cruz “I don’t support legalized marijuana for a whole host of reasons, including the fact that this is a very complex chemical substance.” – Carly Fiorina “I’d say [regulating marijuana] is bad. Medical marijuana is another thing…I think, medical marijuana, 100%” – Donald Trump “States are laboratories of democracy. I want to wait and see what the evidence is.” – Hillary Clinton “I think medical use of marijuana in compassionate cases certainly has been proven to be useful.” – Ben Carson  “I’m against the legalization of marijuana.” - Marco Rubio “[Marijuana legalization]’s not gonna come while I’m here” – Chris Christy 

Marijuana Quotes/References “A harmless giggle” ~ John Lennon “When I was a kid I inhaled frequently. That was the point.” ~ Barack Obama “That is not a drug. It’s a leaf.” ~ Arnold Schwarzenegger “Casual drug users should be taken out and shot.” ~ Chief of LAPD “Music and herb go together. It’s been a long time now I smoked herb. From 1960s when I first start singing.” ~Bob Marley “I enjoy smoking cannabis and see no harm in it.” ~ Jennifer Aniston “Not the quality of life we want.” ~ Chris Christy “You bet I did and I enjoyed it” ~ Michael Bloomberg “The Grass Makes the Other Side of the Hill Look Greener” ~ Lecture Title

“If we think them not enlightened enough to exercise their control with wholesome discretion, the remedy is not to take it away from them but to inform their discretion by education.” ~ Thomas Jefferson

Cannabis Genus Cannabis Sativa and Indica species Rope, clothing, paper, livestock feeds, recreation, religious ceremonies, and medicine Medicinal preparations – China (~2,700 BC) Gout, rheumatism, malaria, constipation, menstrual pain Medieval Time: n/v, epilepsy, inflammation Western Medicine: 1800s – most common analgesic Marijuana Tax Act of 1937 – limited its access

Endocannabinoid System

Endocannabinoid System Produced on demand Dampens excessive neuronal stimulation Found on both (GABA)ergic and glutamatergic neurons Unpredictable

Endocannabinoid System CB1 receptors are concentrated in the hippocampus, association cortices, basal ganglia, cerebellum, spinal cords, and peripheral nerves CB1 receptors are notably absent from the thalamus and brainstem

Marijuana and the munchies Giovanni Marsicano, Univ of Bordeaux THC binds into receptors in the brains olfactory bulbs Smell and taste food more acutely Hypothalamus Ghrelin Stimulates hunger

Marijuana and Pleasure Nucleus accumbens Increasing the release dopamine  pleasure THC is manipulating pathways that already exist our brains

Marijuana and Apathy Cerebral Cortex Prefrontal Cortex Loss of interest Apathy Inability to complete tasks Poor planning and decision making

Cannabidiol (CBD) Cannabidiol (CBD) Does not activate CB1 and CB2 receptors Likely accounts for its lack of psychotropic activity Interacts with many other, non-endocannabinoid signalling systems Inhibits Equibilibrative nucleoside transporter (ENT) Organophosphate G protein coupled receptor GPR55 Transient receptor potential of melastin type 8 (TRPM8) Enhances 5-HT glycine receptors CBD has bi-directional effect on intracellular calcium CBD is multitarget drug

Cannabidiol (CBD) Cannabidiol (CBD) Exerts influence on THC May potentiate some of the beneficial effects of THC Reduces the psychoactivity of THC Counters the functional consequence of CB1 activation Widens the therapeutic window Nambiximols – Used in Multiple Sclerosis ( Equal amount of CBD : THC) Ratio of CBD : THC that matters High CBD : THC ratios are less likely to develop psychotic symptoms Low CBD : THC ratios are more likely to develop psychotic symptoms

Entourage Effect

Howard compares his seizures to electricity and lightning Howard compares his seizures to electricity and lightning. He asks, "What is it like to be split open from the inside by lightning?” He provides one answer: "The actual seizure was when the bolt touched flesh, and in an instant so atomic, so nearly immaterial, nearly incorporeal, that there was almost no before and after . . . and Howard became pure, unconscious energy"

A sudden surge of electrical activity in the brain Seizure A sudden surge of electrical activity in the brain

Epilepsy: 2 or more unprovoked seizures Epilepsy is the fourth most common neurological disorder and affects people of all ages Epilepsy means the same thing as "seizure disorders"  Epilepsy is characterized by unpredictable seizures and can cause other health problems  Epilepsy is a spectrum condition with a wide range of seizure types and control varying from person-to-person

Medically Intractable Epilepsy No single step in treatment defines intractability After each drug failure, the statistical probability of seizure control by the next drug becomes lower, but it never approaches zero

Epileptic Encephalopathies Dravet Syndrome Lennox-Gastaut Syndrome West Syndrome Landau-Kleffner Syndrome

Endocannabinoid System Theory: Endogenous cannabinoids are produced on demand in periods of excessive neuronal excitation CB1 receptors mediates neuronal inhibition by decreasing the calcium influx and increasing potassium efflux

Endocannabinoid System Theory: Seizures: associated with sustained sustained neuronal activation and elevated intracellular calcium Neuronal hyperexcitability that accompanies seizures activity may stimulate endogenous cannabinoid synthesis resulting in activation of CB1 receptor, which can influence seizure activity

Entourage Effect

The Pursuit of Charlotte’s Web

Endogenous cannabinoids CB1 regulates neuronal excitability Neuronal hyperexcitability is associated with seizures No studies –endogenous cannabinoid system in an intact model of epilepsy

Anecdotal data for the use of CBD for the treatment of epilepsy dating back > 150 years Cochrane Database Review for Cannabinoids for Epilepsy by David Gloss and Barbara Vickery Marijuana appears to have anti-epileptic effects in animal models, but the effects in persons with epilepsy is not known Assess the efficacy of Marijuana in the treatment of people with epilepsy Randomized control trials, blinded or not Primary outcome was seizure freedom at 1 year or more or three times the longest interseizure interval 4 Randomized reports

Randomized Studies Study Patient # Dose Efficacy Safety Risk Difference Ames (1985) 12 200mg/day x 4 weeks No differ Mild drowsiness 0.50 Trembly (1990) Placebo x 6 months; CBD x 6 months No data 0.00 Cunha (1980) 15 200-300mg/day for 3-18 weeks 5 Pts seizure free 4 CBD Pts seizure free; 1 Placebo Pt seizure free -0.38 Mechoulam (1978) 9 200mg/day x 3 months 5 Pts with CBD, 2 sz free -0.50

AAN Classification of Therapeutic Trials Class I: Perfect Randomized control trial Class II: Randomized control trial with one or two minor flaws Perfect observational trial (rare) Class III: Randomized control trial with many flaws Most well designed observational trials Class IV: Trials with high risk of bias No better than expert opinion

AAN Classification of Therapeutic Trials 4 Trials from the Cochrane Database Review Class IV Studies The outcomes were not masked, objective, or performed by someone not a member of the treatment team High risk of bias Did not included patients receiving different treatments No measures of statistical precision presented or calculable All studies were low quality

Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders: Report of the Guideline Development Subcommittee of the American Academy of Neurology Barbara S. Koppel, MD, FAAN, John C.M. Brust, MD, FAAN, Terry Fife, MD, FAAN, Jeff Bronstein, MD, PhD, Sarah Youssof, MD, Gary Gronseth, MD, FAAN and David Gloss, MD

Spasticity in patients with MS Central pain and painful spasms in MS Bladder dysfunction in MS Involuntary movements, including tremor, in MS Dyskinesias of Huntington disease, levodopa induced dyskinesias in PD, cervical dystonia, and tics of Tourette syndrome Seizure frequency in epilepsy

Analytic Process Searched Medline, EMBASE, PsychINFO, Web of Science, and Scopus 1,729 abstracts Surveys, case reports/series, non placebo- controlled trials were excluded Reviewed the full text of 63 articles 33 articles met inclusion criteria

Do cannabinoids decrease seizure frequency? No Class I-III studies 2 Class IV studies that did not demonstrate a significant benefit and did not show adverse effects over 3-18 weeks of treatment Conclusion: “data is insufficient to supports or refute the efficacy of cannabinoids for reducing frequency”

The AAN review also concluded that there is not enough information to show if medical marijuana, including smoked medical marijuana, is safe or effective in these neurologic diseases: •Motor symptoms in Huntington’s disease •Tics in Tourette syndrome •Cervical dystonia (abnormal neck movements) •Seizures in epilepsy

There are safety concerns with medical marijuana use There are safety concerns with medical marijuana use. Side effects reported in at least two studies were nausea, increased weakness, behavioral or mood changes, suicidal thoughts or hallucinations, dizziness or fainting symptoms, fatigue, and feelings of intoxication. There was one report of a seizure. Mood changes and suicidal thoughts are of special concern for people with MS, who are at an increased risk for depression or suicide. The studies showed the risk of serious psychological effects is about 1 percent, or one in every 100 people. In general, medical marijuana is prescribed as a treatment for use only when standard treatment has not helped.

American Academy of Neurology (April 2014) “…..scientific research on the use of medical marijuana in brain diseases finds certain forms of medical marijuana can help treat some symptoms of multiple sclerosis (MS), but do not appear to be helpful in treating drug-induced (levodopa) movements in Parkinson’s disease. Not enough evidence was found to show if medical marijuana is helpful in treating motor problems in Huntington’s disease, tics in Tourette syndrome, cervical dystonia and seizures in epilepsy.”

American Epilepsy Society (February 2014) “The recent anecdotal reports of positive effects of the marijuana derivative cannabidiol for some individuals with treatment-resistant epilepsy give reason for hope. However, we must remember that these are only anecdotal reports, and robust scientific evidence for the use of marijuana is lacking. The lack of information does not mean that marijuana is ineffective for epilepsy. It merely means that we do not know if marijuana is a safe and effective treatment for epilepsy, which is why it should be studied using the well-founded research methods that all other effective treatments for epilepsy have undergone.”

The Epilepsy Foundation supports the rights of patients and families living with seizures and epilepsy to access physician directed care, including medical marijuana. The Epilepsy Foundation calls for an end to Drug Enforcement Administration (DEA) restrictions that limit clinical trails and research into medical marijuana for epilepsy. The Epilepsy Foundation believes that an end to seizures should not be determined by one’s zip code.

Marijuana Resource Center: State Laws Related to Marijuana Since 1996, 20 states and Washington, DC have passed laws allowing smoked marijuana to be used for a variety of medical conditions. It is important to recognize that these state marijuana laws do not change the fact that using marijuana continues to be an offense under Federal law.  Nor do these state laws change the criteria or process for FDA approval of safe and effective medications. “www.whitehouse.gov”

Marijuana: Class I Scheduled Drug

Medical marijuana could be legalized in New York this spring: advocates “Proponents of medical pot say newly revised legislation could be approved in Albany this year, which would make New York the 22nd state to legalize medical marijuana. Gov. Cuomo has hinted at his support, but opposition remains in the state Senate.” BY GLENN BLAIN    NEW YORK DAILY NEWS   Published: Sunday, April 27, 2014, 7:44 PM

Compassionate Care Act (07/2014) Allows doctors to prescribe nonsmokable forms of marijuana 23rd state to permit the use of medical marijuana Signed by Andrew Cuomo

New York State Medical Marijuana Program The Medical Marijuana Program will make medical marijuana accessible to patients with conditions including cancer, HIV/AIDS, Lou Gehrig's disease (ALS), Parkinson's disease, multiple sclerosis, damage to the nervous tissue of the spinal cord with objective neurological indication of intractable spasticity, epilepsy, inflammatory bowel disease, neuropathies and Huntington's disease. The law includes these conditions when there is a clinical association with or complication of the condition resulting in cachexia or wasting syndrome, severe or chronic pain, severe nausea, seizures; or severe or persistent muscle spasms. Acting State Health Commissioner Dr. Howard Zucker is also exploring mechanisms that may accelerate access to medical marijuana for children suffering from epilepsy. The Health Commissioner may expand the list of eligible conditions for which medical marijuana certifications may be issued by practitioners. http://www.health.ny.gov/regulations/medical_marijuana/

NJ Senate Bill 2842 Prohibits limitations on number of strains of medical marijuana cultivated, and expands available means of packaging and distribution thereof.** Approved September 10th 2013

Connecticut Allows Medical Marijuana, but Sellers Encounter Hurdles N.Y. / Region |​​NYT Now Connecticut Allows Medical Marijuana, but Sellers Encounter Hurdles By JOSEPH BERGERMAY 1, 2014 http://www.nytimes.com/2014/05/02/nyregion/medical-marijuana-is-legal-in-connecticut-but-not- yet-sold.html?_r=0

23 Legal Medical Marijuana States and DC Alaska Arizona California Colorado Connecticut DC Delaware Hawaii Illinois (2013) Maine Maryland (2014) Massachusettes Michigan Minnesota (2014) Montana Nevada New Hampshire (2013) New Jersey (2010) New York (2014) New Mexico Rhode Island Vermont Washington Oregon

1969 – Gallop Poll : 12% of Americans favored marijuana legalization 2012 – 2013 support for legalization grew 10 %

Is Marijuana Addictive?

Is Marijuana Addictive? Columbia’s Marijuana Research Laboratory Margaret Haney, PhD 1999 – Chronic marijuana users Alternating course of active marijuana versus placebo (21 days) Monitored behavior on closed circuit TV Monitored Sleep patterns, food intake, shift in moods Disturbances in sleep Mood Disturbances Change in appetite Criterion 2 – withdrawal symptoms

Is Marijuana Addictive? Abstinence??? Chronic Users: 15 - 37% are able to maintain abstinence (cocaine) Physical Withdrawal Symptoms (i.e., insomnia, suppressed appetite, etc) Psychological Withdrawal Symptoms (i.e., anxiety, craving) Drives relapse The withdrawal symptoms from marijuana play a role in the inability to maintain abstinence Criterion 4 – unsuccessful efforts to cut down

Is Marijuana Addictive? Alcohol – get into fights; criminal activity, blackouts, seizures, overdose Heroin – overdose; get hepatitis or HIV Crack – seizure or heart attack Crystal Meth – psychotic Marijuana – disorder about the absence of things Unmotivated Cognitively slower Criterion 6 – importance of activities reduced

Is Marijuana Addictive? Yes/No/Probably Most people using marijuana probably don’t experience significant problems But there is a subset of people who do American Psychiatric Association – “ “cannabis use disorder” includes standard addiction signs like a failure to fulfill major roles at work, school, or home; important activities ….. are reduced or given up and afflicts 9% of pot smokers.”

Adolescents and Marijuana Opinions versus Trends As the majority of Americans see marijuana as less risky, the use of marijuana increases Not every user is harmed, but harm from Marijuana does occur.

Adolescents and Marijuana Clinical EEG and Neuroscience “use of marijuana during the teen years negatively impacted : brain structure volume, quality of white matter, and ability to perform cognitive function.”

Center for Injury Epidemiology and Prevention Alcohol: 13 fold increase risk of a MVA Marijuana: doubles the risk of a MVA Marijuana + Alcohol: 24 fold risk of a MVA From 1999 – 2010 involvement in traffic fatalities: Alcohol: stable at 40% Marijuana: tripled from 4-12%

CBD Prescriber Challenges Naturalistic Fallacy “Not everything that is natural is healthy. Arsenic and sharks are natural too” People who will not qualify “ I just had a seizure and I want Marijuana for it” “ My seizures are controlled but I want to use something more natural” Person with an unclear diagnosis of epilepsy Person not on standard anti-epileptic medications/treatments

CBD Prescriber Challenges Perceived Therapeutic Benefits Belief that there is scientific evidence for efficacy and safety Science of convenience Differing opinions not necessarily about facts and evidence At best expert opinion, given lack of scientific evidence Political, Social, and Religious considerations

Risks and Benefits

Are We At A Place of No Return? More users Potentially more treatments Potentially more help for people who really need it Potentially more addicts Potentially more cognitive dysfunction PROGNOSIS More questions More Research

Conclusions The human race has thousands of years of experience with Marijuana A wealth of information regarding the endocannabinoid system Anecdotal evidence Lack of scientific clinical data More work to be done, more questions to answer, and more data to collect. “ An investment in knowledge pays the best interest” Benjamin Franklin