Marijuana in Epilepsy

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

2. “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 

3. 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

4. “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

5. 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

9. Endocannabinoid System

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

11. 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

13. 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

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

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

18. 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

19. 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

20. Entourage Effect

21. 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"

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

23. 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

29. 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

31. Epileptic Encephalopathies • Dravet Syndrome • Lennox-Gastaut Syndrome • West Syndrome • Landau-Kleffner Syndrome

33. 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

34. 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

35. Entourage Effect

36. The Pursuit of Charlotte’s Web

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

39. 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

40. Randomized Studies

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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”

47. 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

48. 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.

49. 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.”

50. 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.”