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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 • • • • 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 • • • • 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 • • • • 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 • 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.