1. Philippe Douyon, MD Epileptologist Northeast Regional Epilepsy Group
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
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. Marijuana and Pleasure
Nucleus accumbens
Increasing the release dopamine  pleasure
THC is manipulating pathways that already exist our brains

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
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. A sudden surge of electrical activity in the brain
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 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
mg/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

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
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.”

51. 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.

52. 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. “

54. Marijuana: Class I Scheduled Drug

55. 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

56. 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

57. 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.

58. 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

59. 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
yet-sold.html?_r=0

61. 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

65. 1969 – Gallop Poll : 12% of Americans favored marijuana legalization
2012 – support for legalization grew 10 %

70. Is Marijuana Addictive?

73. 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

75. Is Marijuana Addictive?
Abstinence???
Chronic Users: % 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

76. 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

77. 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.”

78. 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.

80. 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.”

82. 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%

83. 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

84. 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

85. Risks and Benefits

86. 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

87. 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