Transcript Advances in epilepsy - Epilepsy Foundation of Minnesota

Medical Marijuana for Epilepsy
Midwest Seizure Smart Fall Conference
Epilepsy Foundation of Minnesota
Beverly Wical, MD
Gillette Children’s Specialty Healthcare
Saint Paul, MN
• Disclosures:
• No financial relationships
• Never used marijuana in any form
• However, my husband and I use grass for relaxation
Why Marijuana?
• Antiepileptic medications are the mainstay for the majority
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of patients with epilepsy
Despite increased numbers of new medications, overall
percentage of medically intractable epilepsy remains
significant.
All medications are a complex mix of risk versus benefit
Large gaps remain in our understanding of individual
pharmacogenetics, pharmacokinetics
Targeted therapy for most types of epilepsy remain
elusive
Why Marijuana?
• It has been around a long time
• Recent media reports of remarkable
effectiveness, patient advocacy
• Perception that it is safe, with low risk side effects
• In use for chronic pain, anorexia, muscle spasms,
glaucoma
• “Natural”
Marijuana for epilepsy:
• William Gowers MD: Diseases of the Nervous System
1893, earlier work on epilepsy in 1881
• “Cannibis Indica is occasionally beneficial, both alone and
in combination with bromide…” pg 763 (indica has more
CBD than sativa)
• Other suggestions: digitalis, borax, zinc…
• Bromides most useful… “No salt of bromine has much
less tendency than another to produce acne, and this can
always be prevented or rendered extremely slight by
giving arsenic at the same time.”
Cannabis:
flowering plant
2 main species:
sativa more
activating
indica more
sedating
Cannabis sativa = marijuana
• Composed of more than 500 compounds; new
components continue to be discovered (Radwan 2009).
• Those that are unique to the cannabis plant are called
cannabinoids. ~ 70 - 80 known.
• The principal active component of marijuana is Δ9tetrahydrocannabinol (THC). (Mechoulam 1970).
• Cannabidiol(CBD) is another cannabinoid which has
some of the properties of THC, including the possible
effect of preventing seizures (Howlett 2004, Mechoulom 2007).
Cannabinoids
• THC: psychoactive—produces “high”
• CBD: some behavioral effects (antianxiety,
sedative)
• Endocannabanoid receptor system in the brain affects
synaptic communication; activated by THC
• Modulates eating, anxiety, learning, memory, growth and
development (Devinsky et al, Cannabadiol: Pharmacology and potential
therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia, 2014)
Cannabis sativa CBD
• Proportion of cannabinoids varies from plant
strain to plant strain, and to some extent in each
plant
• CBD only non-THC compound studied in animals
for anti-seizure effect
• Anti epileptic effect found in some seizure
models, not in others.
• Mechanisms of action not clearly understood
Forms of medical marijuana
• Marinol: synthetic dronabinol
• Cesamet: nabilone: synthetic THC…nausea, appetite suppression
• Sativex: oral spray “THC and CBD, as well as other minor cannabinoids and
non-cannab plant components”
• Epidiolex: liquid purified plant derived CBD with no THC; comes in
liquid form. Has orphan drug status from FDA; Phase 3, double blind,
placebo controlled two part study to investigate the dose-ranging
safety and pharmakokinetics, followed by the efficacy and safety of
cannabadiol in children and young adults with Dravet syndrome (not
yet recruiting). LGS trials planned.
• Synthetic CBD: 99% pure, “lab” made. Has orphan drug status
from FDA; Phase 2 trials for Dravet and LGS planned
Forms of medical marijuana
• Plant products, not screened/monitored by FDA
• Charlotte’s Web” hemp strain. Marijuana and hemp
are the same plant genus of same species, cannabis
sativa; hemp yields less than 0.3 % THC in its life cycle.
Bred for a high CBD profile.
• Tested by producers x3 to ensure exact # milligrams of
each major cannabinoid is known
• “Whole plant” interactions between phyto-cannabinoids
and plant terpenes.
• Dosing range 2 – 6 mg CBD/lb typical; start low, go slow;
increases usually weekly…(1 – 3 mg/kg/d)
Human cannabis pharmacology
• Smoking very effective way to absorb drug
• Aerosol/vaporization devices deliver peak plasma
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concentrations in ~ 10 min with bioavailability of ~ 30%
Oil based capsule absorbed very erratically. Bioavailability
~ 6% (due to first-pass metabolism in the liver)
Oral mucosa/under the tongue delivery less variable
absorption but bioavailability still ~ 6%
High degree of variablity between patients
Very lipid soluble, rapid distribution in brain, fat, organs
• May build up a chronic depot of drug, particularly in pts with
increased fat stores.
Human CBD pharmacology
• Extensive metabolism in liver
• Half life 18 – 32 hours
• Uses the enzyme system cytochrome P450
• INHIBITOR of CYP3A, CYP2C: may not be clinically relevant
• CYP3A (benzodiazepines, calcium channel blocking medications,
antivirals, estradiol)
• Phenobarbital, phenytoin, carbamazepine, rifampin, dexamethasone
induce metabolism
• SSRIs (antidepressant/anti-anxiety medication) inhibit
• INDUCER of CYP2B (valproate and clobazam)
• RealmofCaring: beware drug interactions; recommend weekly/biweekly lab checks
Interactions between CBD and AEDs
D. Friedman, MD; NYU, AES Dec 2014
• 33 patients, average age 10
• Average of 3 other AEDs
• 54% were on clobazam; A subset of patients experienced
an increase in the drug
• Serum concentrations of some of the other AEDs were
altered also (VPA, LTG, ZNS, FBM, LEV)—unsure at
present what /how significant changes will be
Friedman, NYU
• CBD can effect co-medications
• Effects may not be seen in all patients
• Frequent monitoring of levels is warranted in children
taking CBD containing products
• More research is needed into potential interactions
Adverse effects
• Drowsiness/Sedation
• Mood changes (irritability)
• Dizziness
• GI upset, dry mouth
• Increased appetite and weight gain
• Decreased appetite and weight loss
• Headache
• Adverse effects of THC may not be quite the same as
CBD
COCHRANE DATABASE
• Cannabinoids for epilepsy
• David Gloss1,*,
• Barbara Vickrey2
• Editorial Group: Cochrane Epilepsy Group
• Published Online: 5 MAR 2014
To assess the efficacy and safety of cannabinoids when used as
monotherapy or add-on treatment for people with epilepsy.
• Included studies: Randomized controlled trials (RCTs) with allocation
concealment that was blinded (single- or double-blinded) OR RCTs
that were unblinded.
• All other study designs, including cohort studies, case-control studies,
outcomes research, case studies, case series and expert opinion
were excluded (21). Small numbers of pts, difficult to interpret
outcome.
• Included:
• People of any age or sex, with epilepsy of any type.
• Any type of marijuana, synthetic or natural THC, cannabinol,
cannabidiol, or combinations that include these agents, for
ingestion or inhalation for the control of seizures. Trials included
using other anti-epileptic medications.
• All major medical literature data bases searched.
• Reviewers contacted the manufacturers of cannabinol or
THC, and experts in the field, for information about any
unpublished or ongoing studies. They hand searched
selected journals.
• Reference lists of retrieved studies were reviewed to
search for additional reports of relevant studies.
No studies assessed the primary outcome--seizure freedom for
12 months or three times the longest seizure-free interval. Four
studies met all the inclusion criteria except the primary outcome.
• In Cunha 1980, there were 15 patients with temporal lobe epilepsy with
secondarily generalized seizures, with at least 1 generalized seizure weekly.
These patients received 200 to 300 mg of cannabidiol daily or placebo. The
patients received the medication for as long as 4.5 months. Of the 8 pts who
rec’d CBD, 4 had “almost complete resolution of convulsive crises,” and 3
were “better”. Only 1 placebo pt got much better. The patients tolerated
cannabidiol without toxicity.
• In Ames 1985, 12 patients institutionalized due to mental retardation with
uncontrolled seizures were given three capsules of sunflower oil (as placebo)
or sunflower oil and 100 mg of cannabidiol for the first week (as treatment).
Thus, patients who were treated received 300 mg of cannabinol daily for the
first week. During the next three weeks (weeks two to four) the patients were
given two capsules, so for those in the treatment arm they received 200 mg of
cannabidiol daily. There were no differences in seizure frequency between the
two groups, although no details were given. The only side effect was mild
drowsiness.
• In Mechoulam 1978, 9 patients were randomized to either 200 mg of
cannabidiol or placebo. Patients were treated with their habitual
medication and either cannabidiol or placebo for three months. 2/4
patients treated with cannabidiol achieved seizure freedom for the three
months of treatment, and none of the 5 treated with placebo were
described as experiencing improvement. No toxic effects were observed.
• The fourth trial was an unpublished abstract from a conference (Trembly
1990). In this abstract 12 patients were treated with a single-blind
placebo for six months followed by double-blind 300 mg of cannabidiol or
placebo in a cross-over trial lasting an additional 12 months. No statistics
were performed but a preliminary review suggested that there was some
reduction in seizure frequency. Further information was provided by
Consroe 1992. Here they stated that 10 patients in the trial did not have
changes in the seizure character or frequency, and did not suffer any side
effects.
• These are 4 very small randomized trials and none of
them measured freedom from seizures at 12 months or
three times the greatest inter-seizure period, or even
responder rate at six months.
• Quality of the evidence
• Under contemporary standards, all four trials are low
quality and have to be at high risk for bias. The largest
study was of 15 patients. One of the studies was an
abstract that had additional details in the chapter of a
book, and another was a letter to the editor.
Meta analysis conclusion:
• No reliable conclusions can be drawn at present
regarding the efficacy of cannabinoids as a treatment for
epilepsy. The dose of 200 to 300 mg daily of cannabidiol
may be safe, although the number of patients treated at
this dose is small and, except for one study, the treatment
was only for a short period of time.
Other reports:
• Realm of Caring Foundation: 85% of initial cohort of
children using CBD have a reduction in seizures of 50%
or more (per Epilepsy Foundation of CO site)
• Margaret Gedde, MD—physician in CO—estimates ~
25% of children have a dramatic improvement; and
another 50% have some improvement.
• Bonni Goldstein, MD, medical director at marijuana
technology co “Ghost Group” in CA says 70-75% of pts
saw a “reduction in seizures” according to early data
Epidiolex initial safety and efficacy trial
O Devinsky, MD; NYU, AES 2014
• 23 children with “treatment resistant epilepsy” (Dravet,
LGS), average age 10
• 4 week baseline, then purified 98% oil-based CBD extract
• Known and constant composition
• 5 mg/kg/d with other AEDs to start
• Gradually increased to 25 mg/kg/d
• After 12 weeks: 39% had > 50% reduction in seiures
• Median reduction of 32%
• 3/9 Dravet, 1/14 other: SEIZURE FREE
• Adverse effects mild to moderate: somnolence, fatigue,
changes in AED levels, wt gain or loss, diarrhea
Retrospective review cannabis use
K Chapman MD; U of CO; AES, 2014
• 58 children, average age 7
• “catastrophic epilepsy”
• Artisanal oral cannabis extracts
• ~ 33% reported seizure reduction 50% or >
• 16 children had pre and during treatment EEGs; 2 were
better, 14 were not.
• Response rate did not differ with various strains of
cannabis
• ***Families who had moved to CO for CBD rx were 3
times as likely to report >50% reduction in seizures than
families who already lived in CO
U of CO: Chapman, et al
• Adverse effects 47%
• 21%: new seizures or increased seizures
• 14% somnolence or fatigue
• 10% developmental regression; 1 patient needed intubation; 1
death
• “This substantial gap between the clinical observations
and various anecdotal reports highlighted in popular
media underscores the desparated need shared by the
entire epilepsy community for robust scientific evidence
regarding the potential benefit and risks of marijuana in
people with epilepsy.” Keith Chapman, MD
Report of a parent survey of cannabidiol-enriched cannabis use in
pediatric treatment-resistant epilepsy.
Porter BE, Jacobson C. Epilepsy and Behavior; 2013
• A survey was presented to 150 parents belonging to a Facebook group dedicated to
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sharing information about the use of cannabidiol-enriched cannabis to treat their child's
seizures. 19 responses met the following inclusion criteria for the study: a diagnosis of
epilepsy and current use of cannabidiol-enriched cannabis. 13 Dravet syndrome, 4 had
Doose syndrome, and one each had Lennox-Gastaut syndrome and idiopathic
epilepsy. The average number of antiepileptic drugs (AEDs) tried before using
cannabidiol-enriched cannabis was 12.
16/19 (84%) reported a reduction in their child's seizure frequency while taking
cannabidiol-enriched cannabis. 2/19 (11%) reported complete seizure freedom, 8/19
(42%) reported a greater than 80% reduction in seizure frequency, and 6/19 (32%)
reported a 25-60% seizure reduction.
Other beneficial effects included increased alertness, better mood, and improved sleep.
Side effects included drowsiness and fatigue.
Parents are using cannabidiol-enriched cannabis as a treatment for their children with
treatment-resistant epilepsy. Because of the increasing number of states that allow
access to medical cannabis, its use will likely be a growing concern for the epilepsy
community. Safety and tolerability data for cannabidiol-enriched cannabis use among
children are not available.
Why did the other 131 parents not respond?
Long-Term Effects of Cannabis on Brain Structure
Giovanni Battistella, Eleonora Fornari, Jean-MarieAnnoni, HaithemChtioui,, Kim Dao, Marie Fabritius, Bernard Favrat,
Jean-Frédéric Mall, Philippe Maeder and Christian Giroud…Neuropsychopharmacology
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Advance online publication 16 April 2014
• The dose-dependent toxicity of the main psychoactive component of cannabis in brain
regions rich in cannabinoid CB1 receptors is well known in animal studies. However,
research in humans does not show common findings across studies regarding the brain
regions that are affected after long-term exposure to cannabis. In the present study, we
investigate (using Voxel-based Morphometry) gray matter changes in a group of regular
cannabis smokers in comparison with a group of occasional smokers matched by the years
of cannabis use. We provide evidence that regular cannabis use is
associated with gray matter volume reduction in the medial temporal
cortex, temporal pole, parahippocampal gyrus, insula, and
orbitofrontal cortex; these regions are rich in cannabinoid CB1 receptors and
functionally associated with motivational, emotional, and affective processing. Furthermore,
these changes correlate with the frequency of cannabis use in the 3 months before inclusion
in the study. The age of onset of drug use also influences the magnitude
of these changes. Significant gray matter volume reduction could result either from
heavy consumption unrelated to the age of onset or instead from recreational cannabis use
initiated at an adolescent age. In contrast, the larger gray matter volume detected in the
cerebellum of regular smokers without any correlation with the monthly consumption of
cannabis may be related to developmental (ontogenic) processes that occur in adolescence.
Cannabis Use Is Quantitatively Associated with Nucleus Accumbens and
Amygdala Abnormalities in Young Adult Recreational Users
Jodi M. Gilman,,John K. Kuster, Sang Lee, Myung Joo Lee, Byoung Woo Kim, Nikos Makris, Andre van der Kouwe, Anne
J. Blood, and Hans C. Breiter†…Journal of Neuroscience
• We collected high-resolution MRI scans on young adult recreational
marijuana users and nonusing controls and conducted three
independent analyses of morphometry in these structures: (1) gray
matter density using voxel-based morphometry, (2) volume (total brain
and regional volumes), and (3) shape (surface morphometry). Gray
matter density analyses revealed greater gray matter density in
marijuana users than in control participants in the left nucleus
accumbens extending to subcallosal cortex, hypothalamus,
sublenticular extended amygdala, and left amygdala, even after
controlling for age, sex, alcohol use, and cigarette smoking. Trendlevel effects were observed for a volume increase in the left nucleus
accumbens only. Significant shape differences were detected in the
left nucleus accumbens and right amygdala. The left nucleus
accumbens showed salient exposure-dependent alterations across all
three measures and an altered multimodal relationship across
measures in the marijuana group. These data suggest that
marijuana exposure, even in young recreational users, is
associated with exposure-dependent alterations of the
neural matrix of core reward structures and is consistent
with animal studies of changes in dendritic arborization.
Other potential uses of CBD
• Newborn hypoxic ischemic brain injury
• Psychosis, cognitive function in schizophrenia
• Anxiety disorders
• Addictive behaviors (heroin, amphetamine, marijuana)
MN and MJ:
• Deadline for submission of implementation report 2/15
• Patient application process “sometime after”
• Selected manufacturers to supply product by July 2015
• 6 mo delay allowed if delay in selecting manufacturer OR delay in
supply of manufacturer
• Patients in bordering states are not allowed to participate
in MN program (interstate commerce laws)
• 8 distribution centers around the state
• $200 to join registry ($150 if on SSI, MA, MinnCare)
• “Patients will also pay a yet-to-be determined price for
medical cannabis products”…
Cost of CBD: for a 55 lb child
~300 - 600 mg/d
• No insurance coverage
• Charlotte’s Web cost estimates $100 – 600/mo—doses
recommended are 1 – 3/kg; Epidiolex trial closer to 12/kg
• Sativex (nasal spray for MS) in Canada ~ $ 300/mo (US)
• “Real Scientific Hemp Oil (24.5% CBD) $649 for 10 gm
• 4 – 8 day supply
• Ultra CBD oil: $45 for 200 mg; ~ 90 ~ $180/ day
Medical marijuana for pediatric epilepsy
Effects on developing brain
unknown; no long term
outcome studies or even
short outcome studies are
available
Actual efficacy is unknown,
but small series, anectdotal
reports very promising
Potential for drug
interactions uncertain, but
may be clinically significant
Dosing in children unclear
• All new therapies must be carefully
and continually evaluated for both
safety and efficacy.
• Therapies currently in use need
ongoing scrutiny as well.