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Cannabinoids: a pediatric perspective Christopher Campbell PGY2 Pediatric Pharmacy Resident Augusta University Medical Center University of Georgia College of Pharmacy Disclosure I do not have (nor does any immediate family member have) actual or potential conflict of interest, within the last twelve months; a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity; or any affiliation with an organization whose philosophy could potentially bias my presentation. Objectives 1. Describe the clinical pharmacology of medical cannabinoids in a pediatric patient population. 2. Identify the evolving regulatory issues of cannabinoid use in the United States. 3. Analyze current clinical data for cannabinoid use in a pediatric patient. 4. Discuss pediatric considerations regarding overuse and misuse of cannabinoids. Definitions Cannabis ◦ Hemp plant from which marijuana is derived ◦ 3 species (C. sativa, C. indica, C. ruderalis) Marijuana ◦ Dried leaves, flowers, stems, and seeds from the hemp plant Cannabinoid ◦ Chemicals that interact with specific receptors located within different parts of the central nervous system http://www.drugabuse.gov/publications/drugfacts/marijuana Types of Cannabinoids delta – 9 – tetrahydrocannabinol (THC) ◦ The psychoactive cannabinoid most commonly associated with marijuana Cannabigerols (CBG) Cannabichromenes (CBC) Cannabidiols (CBD) Cannbinol (CBN) and cannabinodiol (CBDL) Others (cannabicyclol (CBL), cannabielsoin (CBE), cannabitriol (CBT) http://learnaboutmarijuanawa.org/factsheets/cannabinoids.htm What’s the difference? Cannabinoids Psychoactive Not Psychoactive • Cannabinol (CBN) • Cannabinodiol (CBDL) • delta – 9 – tetrahydrocannabinol (THC) • Cannabigerols (CBG) • Cannabichromenes (CBC) • Cannabidiols (CBD) http://learnaboutmarijuanawa.org/factsheets/cannabinoids.htm Endocannabinoid System Anandamide 1992: naturally occurring substance that binds to CB1 receptors was discovered Shown to have inhibitory effects on serotonin type 3 receptors (antiemetic, analgesia, etc) 2 receptors types found in early 1990s CB1 Expressed on presynaptic peripheral and central nerve terminals Some exposure on peripheral organs CB2 Concentrated in peripheral tissues and immune cells Baron EP. Headache. June 2015 Endocannabinoid System CB1 CB2 One of the most abundant found in the peripheral and central nervous system Primarily located on immune cells and tissues Distributed throughout the brain: Pleasure Memory Thought Concentration Sensory and time perceptions Coordinated movement When activated, affect inflammatory and immunosuppressive activity Sparsely found in the cardiopulmonary centers in the brainstem Baron EP. Headache. June 2015 Control release of cytokines and cell migration Cannabinoid Receptor Effects Physiologic effects • Tachycardia, hypertension, dry mouth and throat Psychologic effects • Elation, euphoria, increased appetite, heightened perception, paranoia, anxiety, irritability, impaired short term memory, poor coordination and balance Baron EP. Headache. June 2015 http://www.nature.com/nrc/journal/v3/n10/images/nrc1188-i1.jpg http://www.tokeofthetown.com/2012/01/worth_repeating_marijuana_treats_anxiety_and_depre.php THC vs Cannabidiol Friedman D, Devinsky O. N Engl J Med 373; 11 THC vs Cannabidiol CANNABIDIOL ◦ Isolated in 1963 ◦ Most abundant cannabinoid, contributing up to 40% of cannabis resin. ◦ Does not appear to bind to either CB1 or CB2 ◦ Interacts with ion channels, enzymes, and other receptors ◦ Inhibits cyclooxygenase and lipoxygenase – antiinflammatory and analgesic effects ◦ May be an inverse agonist because several studies have shown that it decreases the psychotropic activity of THC ◦ May enhance the activity of the endogenous cannabinoid, anandamide ◦ May have an anti-anxiety effect http://learnaboutmarijuanawa.org/factsheets/cannabinoids.ht m Baron EP. Headache. June 2015 THC ◦ Isolated in 1964 ◦ Partial agonist at both CB1 and CB2 receptors but also acts at non-CB receptors ◦ Possible pro-convulsant ◦ Deleterious effects on brain development and cognition Pharmacokinetics THC • Onset: 30 minutes after inhalation and 2 to 4 hours after ingestion • Half-life: 7 days • Large volume of distribution CBD • Onset: similar • Half-life: 9 hours • Bioavailability: 13 – 19% • Metabolized by CYP3A2/4 enzymes Borgelt LM. Pharmacotherapy 2013; 33(2):195-209 Ashton, CH. The British Journal of Psychiatry Feb 2001, 178 (2) 101-106 A brief history lesson… Cannabinoid History Hemp plants used as early as 4000 BC in Western and Central Asia Use diminished with the introduction of phenobarbital (1912) and phenytoin (1937) 1851: United States Pharmacopeia classified marijuana as a legitimate medical compound 1400 – 2000 BC: Medical uses documented Baron EP. Headache. June 2015 Borgelt LM. Pharmacotherapy 2013; 33(2):195-209 Friedman D, Devinsky O. N Engl J Med 373; 11 Victorian-era neurologists used Indian hemp to treat epilepsy and reported success Regulatory History Marihuana Tax Act of 1937 • Cannabis identified as a drug of abuse by minority and low income populations in 1930’s 1930’s: Drug of Abuse Baron EP. Headache. June 2015 • Heavy tax for cannabis and hemp use for medicinal or industrial uses • Failure to comply was faced with prison and large fines • Cannabis preparations are removed from the United States Pharmacopoeia and National Formulary 1941: USP/NF Regulatory History Recreational marijuana use surges in 1960’s and early 1970’s 1988: failed attempt to reschedule to Schedule II Controlled Substances Act of 1970: cannabis is labelled as a Schedule 1 substance also with heroin and LSD Baron EP. Headache. June 2015 2001 and 2006: two more failed attempts 2001 Department of Health and Human Services filed a patent for cannabinoids awarded in 2003 for “cannabinoids as antioxidants and neuroprotectants” 2015: federal judges are currently reviewing whether reclassification is warranted http://patientsoutoftime.org/wp-content/uploads/2015/01/cannabis-states.png http://america.aljazeera.com/.jpg http://www.lexisnexis.com/Communities/cfsfile.ashx/__key/communityserver-blogs-components-weblogfiles/00-00-00-0022/1641.potmap.jpg Georgia Marijuana Act “Haleigh’s Hope Act” signed into law in April 2015 by Governor Nathan Deal Allows for possession of up to 20 ounces of cannabis oil following a physician order if a patient suffers from 8 serious medical conditions Oil must not contain more than 5% THC Georgia’s medical marijuana law does not legalize the production or sale of marijuana, it simply decriminalizes its possession by certain qualified individuals. http://www.georgiacannabis.org/obtain-medical-marijuana/ http://www.cnn.com/2015/04/16/us/georgia-medical-marijuana-bill-signing-haleigh-cox/ http://www.ajc.com/news/news/medical-marijuana-bill-georgia-facts/nkwWM/ Cancer Crohn’s disease Lou Gehrig’s disease Mitochondrial disease Multiple sclerosis Parkinson’s disease Seizure disorders Sickle cell disease Legal Marijuana* *According to the Federal government Investigational New Drug Program – closed in 1992 12 patients allowed to continue; two patients remain in the program Federally approved source of research-grade cannabis at a farm at the University of Mississippi Cannabis-derived pharmaceuticals ◦ Dronabinol (schedule III) and Nabilone (schedule II) Treatment of nausea and vomiting associated with cancer Treatment of anorexia associated with weight loss in patients with acquired immune deficiency syndrome (dronabinol) Nabiximols (not FDA approved) Symptomatic relief of spasticity in adults with multiple sclerosis Symptomatic relief of neuropathic pain in patients with MS Intractable cancer pain Baron EP. Headache. June 2015 Lexicomp. “Dronabinol”. Accessed October 13, 2015. Lexicomp. “Nabilone”. Accessed October 13, 2015 American Academy of Pediatrics The federal and state governments should establish robust health surveillance regarding the impact of marijuana, particularly on children and adolescents. In states that have legalized marijuana for recreational use, the AAP strongly recommends strict enforcement of rules and regulations that limit access, marketing and advertising to youth. Research and development should be conducted of pharmaceutical cannabinoids. The AAP recommends changing marijuana from a DEA Schedule 1 to a DEA Schedule 2 to facilitate this research. Where marijuana is sold legally, either for medicinal or recreational purposes, it should be contained in child-proof packaging to prevent accidental ingestion. https://www.aap.org/en-us/about-the-aap/aap-press-room/pages/American-Academy-ofPediatrics-Reaffirms-Opposition-to-Legalizing-Marijuana-for-Recreational-or-MedicalUse.aspx The AAP discourages adults from using marijuana in the presence of children because of the influence of role modeling by adults on child and adolescent behavior. End of the history lesson… Baron EP. Headache. June 2015 Pediatric Cannabinoid (Possible) Indications Epilepsy Attention-deficit hyperactivity disorder Autism spectrum disorder Perinatal Brain Injury Neuroblastoma Why cannabinoids in epilepsy? 1) Endocannabinoid system ◦ Anandamide can affect excitability in the neuronal networks by activating the transient receptor potential (TRP) cation channel 2) Epilepsy patients have defects in endocannabinoid ◦ Patients with newly diagnosed temporal-lobe epilepsy had significantly lower levels of anandamide in CSF than healthy controls ◦ Tissue from patients undergoing surgery for epilepsy had lower levels of CB1 receptor messenger RNA vs. cadavers without epilepsy 3) Found that mice, anandamide levels rise after seizures suggesting a role in anti-seizure activity Friedman D, Devinsky O. N Engl J Med 373; 11 CBD and Antiepileptic Effects At high concentrations, activates the nuclear peroxisome proliferatoractivated receptor-gamma Inhibits the cellular uptake and degradation of the endocannabinoid anandamide Modulates intracellular calcium concentration and inhibits Ttype calcium channels Cilio MR et al. Epilepsia. 2014. 55 (6): 787-790 Cannabinoids for epilepsy: Cochrane Review Objective • Assess the efficacy of marijuana, or one of marijuana’s constituents in the treatment of people with epilepsy Inclusion • 4 randomized reports including a total of 48 patients, each of which used cannabidiol as the treatment agent Results • No reliable conclusions on efficacy but 200 – 300 mg daily of cannabidiol was safely administered to a small number of patients for a short period of time Gloss D, Vickrey B. Cochrane Database of Systematic Reviews 2012, Issue 6 American Academy of Neurology Conclude that “for patients with epilepsy, data are insufficient to support or refute the efficacy of cannabinoids for reducing seizure frequency” There is NOT sufficient evidence to prescribe CBD or recommend self-treatment with smoked marijuana Koppel BS et al. Neurology 2014; 82:1556-1563 Why are parents using cannabis? Anecdotal cases of children successfully treated with medical marijuana (CBD enriched preparations) Cilio MR et al. Epilepsia. 2014. 55 (6): 787-790 Prominent internet and national media attention Belief that treatments derived from natural products are safer or more effective is common and potentially dangerous Charlotte Charlotte is a little girl from Colorado with Dravet syndrome Frequent bouts of febrile and afebrile status epilepticus Failed multiple medications: ◦ Levetiracetam, oxcarbazepine, topiramate, zonisamide, valproate, clobazam, clonazepam, and diazepam At 5 years of age, had significant cognitive and motor delays, required a feeding tube, and needed full assistance with activities of daily living 50 generalized tonic-clonic seizures per day http://www.cnn.com/2013/08/07/health/charlotte-child-medical-marijuana/ Charlotte’s Web A high concentration CBD/THC strain of cannabis produced by a medical marijuana group in Colorado Charlotte’s Web, supplied by Realm of Caring, is based out of Colorado and parents and families are moving there to attempt treatment Parents began giving Charlotte low doses of plant extract and slowly increased the dose over time Month 3: >90% reduction in generalized tonicclonic seizures and weaned from other AEDs http://www.cnn.com/2013/08/07/health/charlotte-child-medical-marijuana/ Month 20: 2-3 nocturnal generalized tonic-clonic seizures per month, feeds and drinks by mouth by herself and autistic behaviors have improvement, walking and talking Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy Methods: • Retrospective chart review of children and adolescents who were given oral cannabis extracts (OCE) for treatment of their epilepsy • Seizure response was based on parental report of total seizure frequency prior to initiating OCE treatment • Deemed a responder if parental report of >50% reduction in seizure frequency Patients: • 75 patients (45.3% male) • Mean age 7.33; range 0.5 – 18.25 Results • 43/75 (57%) of parents reported some improvement • 25/75 (33%) reported to have >50% reduction in seizures • 2/75 (0.3%) reported to be seizure free by their last follow up • No difference in response rate between different types of oral cannabis extract (CBD, CBD+other OCE, THC only, other) Press CA et al. Epilepsy and Behavior 45 (2015) 49-52 Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy Other Improvements Adverse Effects • Improved behavior/alertness in 25/75 (33%) • Improved language 8/75 (11%) • Improved motor skills 8/75 (11%) • Increased seizures 10/75 (13%) • Somnolence/fatigue 9/75 (12%) • GI symptoms 8/75 (11%) Press CA et al. Epilepsy and Behavior 45 (2015) 49-52 Parent survey of cannabidiolenriched cannabis use Stanford University Survey of 24 questions Diagnosis and seizure types Parental-reported effect of cannabidiol-enriched cannabis on the child’s seizure frequency and side effects Administered to Facebook group of 150 parents supporting the use of cannabidiol-enriched cannabis to treat children with treatment-resistant epilepsy Porter BE et al. Epilepsy Behav. 2013; 29(3):574-577 Parent survey of cannabidiolenriched cannabis use Population Demographics Results • Age range: 2 – 16 years old • Seizure Types: • Dravet syndrome = 13 • Doose = 4 • Lennox-Gastaut syndrome = 1 • Idiopathic early-onset epilepsy = 1 • 18/19 patients experienced treatment resistant epilepsy for more than 3 years before trying CBD • Unsuccessfully tried median 12 other antiepileptics • Seizure Frequency pre-CBD: 2 per week to 250 per day • 16/19 (84%) reported a reduction in their child’s seizure frequency • 2/16 reported to be seizure free • 8/16 reported a greater than 80% reduction in seizure frequency • 3/16 reported a greater than 50% reduction in seizure frequency • 12/19 patients weaned their child from another AED • Other effects: • Better mood (15/19, 79%) • Increased alertness (14/19, 74%) • Better sleep (13/19, 68%) • Drowsiness (7/19, 37%) • Fatigue (3/19, 16%) Intervention • Dose Ranges: 0.5 mg/kg/day to 28.6 mg/kg/day • THC: 0 to 0.8mg/kg/day Porter BE et al. Epilepsy Behav. 2013; 29(3):574-577 Parent survey of cannabidiolenriched cannabis use Cannot verify: Dose Response Parents have an interest in using CBD for their children’s seizures which may select for positive outcomes Conclusions: Parents report reduced seizures in a refractory group of childhood epilepsies which warrants further study Favorable side effect profile with potential benefits in cognition and mood Porter BE et al. Epilepsy Behav. 2013; 29(3):574-577 Perceived efficacy of cannabidiol enriched cannabis extracts Population Demographics • 117 respondents, median age 6 (3-10) • Number of failed medications, median 8 (4-12) • Failed ketogenic diet therapy before CBD exposure, n = 53 (45.3%) • Epilepsy Conditions, n (%) • Infantile spasms, 45 (38.5) • Lennox-Gastaut syndrome, 24 (20.5) • Infantile spasms and/or Lennox-Gastaut syndrome, 53 (45.2) • Dravet syndrome, 15 (12.8) • Other/unknown, 44 (37.6) CBD Exposure • Duration, months, median 6.8 (3.8-9.8) • Continued CBD treatment at time of survey, 93% • CBD product with at least 15:1 ratio of CBD to THC, 83.5% • CBD dosage, mg/kg/day, n = 46 median 4.3 (2.9 – 7.5) • Number of concomitant medications 2 (0 – 3) Hussain SA. Epilepsy and Behavior 47 (2015) 138-141 Results • Efficacy • N = 100 (85%) reported a reduction in seizure frequency • N = 16 (14%) reported complete seizure freedom • 86% reported changes in frequency within 14 days Clinicaltrials.gov 88 studies found related to “cannabidiol” 30 studies related to epilepsy 6 studies related to dementia/delirium 14 studies related to autoimmune diseases 4 studies found related to “cannabidiol AND pediatrics” Many more for Dravet’s syndrome, Lennox—Gastaut syndrome, and cannabidiol Clinicaltrials.gov Cannabidiol Use at Augusta University http://www.gru.edu/research/studies/cannabidiol/images/doctor.png http://www.gru.edu/research/studies/cannabidiol/release1214.php Epidiolex® (cannabidiol) in Treatment Resistant Epilepsy Objective: • Ten centers have independent FDA approved open-label Expanded Access Programs and have treated children and young adults with treatment-resistant epilepsies with pure CBD Intervention: • Open-label cannabidiol given as a liquid and titrated to a daily dose of 25mg/kg Results: • 123 patients with 12 weeks of continuous exposure • Median reduction of -46% at week 12 • Dravet patients: reduction of -50% by week 12 • LGS: reduction of -52% by week 12 • Adverse reactions: somnolence (21%), diarrhea (17%), fatigue (17%), and decreased appetite (16%) Devinsky O. AAN 67th Annual Meeting Abstract. April 13, 2015 Clinicaltrials.gov A Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P) in Children and Young Adults With Dravet Syndrome • Randomized, double blind, placebo controlled trial • Primary Outcome Measures: • Mean percentage change from baseline in convulsive seizure frequency during the maintenance period (Day 15 to the end of the evaluable period) • Secondary Outcome Measures: • Convulsive seizure free • Adverse effects • Caregiver Global Impression of Change (CGIC) • GW Pharmaceuticals A Study to Investigate the Efficacy and Safety of Cannabidiol (GWP42003-P; CBD) as Adjunctive Treatment for Seizures Associated With Lennox-Gastaut Syndrome in Children and Adults Clinicaltrials.gov ADHD and Autism Sparse data Gaining popularity particularly on social media sites Mice models have demonstrated altered endocannabinoid signaling in the CNS and reported as a promising role for cannabis as treatment by the mainstream media https://www.facebook.com/Moms4MJ?fref=nf Dronabinol in Autism Case Report Six year old boy with early infant autism Intervention: dronabinol drops, one drop (0.62mg) in the morning which was gradually increased day to day Symptom severity was determined by using the ABC (Aberrant Behavior Checklist) Results: Maximum tolerated dose effect reached (2 drops in the AM, 1 midday, 3 drops in the evening = 3.62 mg/day) ABC subscales significant decreased over 6 months Kurz R et al. Cannabinoids 2010; 5(4):4-6 Dronabinol Self-Injurious Behavior (SIB) Case Series Patients: • 10 mentally handicapped adolescent patients exhibiting treatmentresistant self-injurious behavior • Failed previous medications (range 4 -17) Intervention: • dronabinol 2.5 mg BID – 5 mg QID Results: • 7/10 had a significant improvement in their SIB and overall mood/well being as reported by caregivers • 2/10 experienced agitation and drug was discontinued • Follow up 6 months later, patients still had benefit Kruger T. J Dev Behav Pediatr. 2006; 27:433 Perinatal Brain Injury Can be induced by: Neonatal asphyxia Neonatal hypoxia-ischemic encephalopathy (HIE) Stroke-induced focal ischemia Results in: Glutamate excitoxicity Neuroinflammation Oxidative stress Apoptotic-necrotic cell death Brain lesions Long-lasting functional impairment Current therapies for HIE Hypothermia – only clinical intervention that has shown some effectiveness in reducing brain damage Magnesium sulfate – inhibits glutamate excitotoxicity N-acetylcysteine allopurinol – reduce oxidative stress Minocycline – modulates the neuroinflammatory response Endocannabinoid system responds early to neuronal injury Prevents glutamate excitotoxicity, activation of cell death pathways, infiltration of circulating leukocytes across the blood brain barrier Fernandez-Lopez D. et al. Brain Sci 2013, 3, 1043-1059 Experimental Models Newborn hypoxic-ischemic brain damage in piglets Newborn hypoxic-ischemic brain damage in mice Pazos MR. et al. Neuropharmacology 71 (2013) 282-291 Castillo A. et al. Neurobiology of Desease4 37 (2010) 434 - 440 • CBD reduced the density of necrotic neurons • Modulation of inflammation and oxidative stress • CBD reduced cell death in immature mouse brain • Modulation of glutamine release, cytokine production, and COX-2 expression Neuroblastoma Proposed antitumor activity of cannabis preparations Vanilloid receptors/peroxisome proliferator activated receptors In vitro Testing CBD and THC reduced viability of neuroblastoma cells in a dose- and timedependent way CBD treatment had a significantly better response vs. THC treated cells in a single cell line (p = 0.0004) In vivo Testing Mice were treated with daily intraperitoneal injections of THC, cannabadiol, ethanol, or untreated Results: THC and CBD groups has significantly reduced tumor growth Fisher T. Current Oncology. 2016. 23: S15-S22 What is the harm? Harm to Marijuana 50-70% more carcinogenic ingredients than cigarette smoke that can lead to lung cancer Cardiac adverse effects tachycardia, hypertension, syncope, palpitations, transient ischemic attacks Central nervous system adverse effects psychological dysfunction, memory formation, depersonalization, paranoia, anxiety, changes in mood Gateway drug Seamon MJ. Am J Health-Syst Pharm 2007 (64): 1037-1044 Emergency Department Visits Three groups of patients: 1) exacerbation of chronic issues (asthma) because of smoking marijuana 2) acute effects from eating too many edibles ◦ tachycardia, hallucinations, or cyclic vomiting 3) children admitted to the ED Berger E. Annals of Emergency Medicine. 2014 (64) 4 Pediatric Marijuana Exposures in a Medical Marijuana State Methods and Objective • Retrospective cohort study from January 1, 2005 through December 31, 2011. • To compare the proportion of marijuana ingestions by young children who sought care at a children’s hospital in Colorado before and after modification of drug enforcement laws in October 2009 regarding medical marijuana possession Patients Population • 1378 patients younger than 12 years old evaluated for unintentional ingestions: • 790 patients before September 30, 2009 and 588 patients after October 1, 2009 • Median age was 2.6 years (IQ range, 1.6 – 3.0) • 56.8% male Wang GS. et al. JAMA Pediatrics 2013 (167) 7 Colorado Case In 2009, the state modified enforcement efforts Medical Marijuana passes in 2000 No ED visits by children in Colorado for marijuana exposure Berger E. Annals of Emergency Medicine. 2014 (64) 4 Mid 2009 – 2011 – 14 pediatric marijuana exposure visits Pediatric Marijuana Exposures in a Medical Marijuana State Results: • Annual ED census of 65,000 visits: • 0 of 790 (0%) to 14 of 588 (2.4%) (p<0.001) • Those exposed: range 8mo to 12 years, 64.2% males • Symptoms included: lethargy (9), ataxia (1), respiratory insufficiency (1) • 8 admissions • 2 admissions to the ICU • 8 of 14 cases involved medical marijuana and 7 were from food products Wang GS. et al. JAMA Pediatrics 2013 (167) 7 Poison Control Centers Pediatric marijuana exposures call volume increased by 30.3% between 2005 and 2011 in the states where laws decriminalizing marijuana has been passed Most parents and grandparents say the child got into an edible Colorado State of the State address in early January “Just as we must implement the voters’ wishes on marijuana, we are obligated to make sure that children and parents understand brain development and the risks of underage use” – Governor John Hickenlooper Berger E. Annals of Emergency Medicine. 2014 (64) 4 Packaging and Labeling Products have labels and packaging that can be easily mistaken for conventional food products by young children Most products lack regulatory and safety packaging http://cdn.shopify.com/s/files/1/0754/5733/products/bottle_large.gif?v=1422330668 http://www.drugfree.org/wp-content/uploads/2011/07/Pill-bottles-7-8-11-2.jpg https://upload.wikimedia.org/wikipedia/commons/4/43/Surgeon_General's_warning_cigarettes.jpg Medical Marijuana and the Role of the Pharmacist Patient and Family Counseling Many of the detrimental neurocognitive effects of acute marijuana intoxication have a hangover effect with effects lasting at least 1 day after last use and with subtle effects even measurable 1 month later among adolescents Doubling of the odds of fatal motor vehicle accident for adolescents and adults driving under the influence of cannabis Adolescent use may be associated with a decline in intelligence quotient Adverse psychiatric issues with heavy use Medical Professional Education Educate on the differences between cannabinoids and help remove the stigma around appropriate and legal use of cannabidiol products CBD potent inhibitor of CYP 2B6, 2C8, 2C9, 2C19, and 3A4 Hadland SE et al. J Dev Behav Pediatr 36:115-123, 2015 Conclusions Medical cannabinoids may have a place in pediatric care especially in refractory epileptic states Current regulation of cannabinoid use is changing allowing for better access to medications and increased research in these areas The legalization and widespread availability also increases the risk of unintentional and intentional administration in children leading to an increase in emergency room visits Pharmacists should support continued research in this area and offer counseling and assistance with medication management Toward Drugs Derived from Cannabis Methods • Controlled trial of 9 patients with uncontrolled temporal lobe epilepsy who had failed treatment with multiple medications Intervention • Four patients in cannabidiol arm: 200 mg daily for 3 months • Five patients in placebo arm: placebo daily for 3 months Results • Group 1: two patients seizure-free for the entire three months, one patient with partial improvement • Group 2: no patient showed improvement Mechoulam R. Carlini EA. Naturwissenschaften 65, 174-179 (1978) Chronic Administration of Cannabidiol to Healthy Volunteers and Epileptic Patients Population: • 16 subjects aged 22 – 35 • 11 men and 5 women • Average weight of 65 kg Intervention • Group 1: Cannabidiol 3 mg/kg daily for 30 days • Group 2: Placebo daily for 30 days Results • Group 1: somnolence (2) • Group 2: withdrew (1), palpitations (1) • Neurological and clinical examinations, EEG and ECG tracings, blood and urine analyses were within normal limits Cunha JM et al. Pharmacology 21: 175-185 (1980) Chronic Administration of Cannabidiol to Healthy Volunteers and Epileptic Patients Population • 15 epileptic patients, 11 women and 4 men, aged 14-49 (average 24) • Patients with frequent convulsions for at least 1 year who were not reacting satisfactorily to the prescribed antiepileptic drugs they were receiving Intervention • Group 1: cannabidiol 200mg – 300mg daily • Group 2: placebo • Scored 0-3 : 0 = complete improvement, 1 = partial improvement, 2 = small improvement, 3 = without improvement Results • Group 1: 50% (4 of 8 patients) showed complete improvement (median = 0), 1 patient with partial improvement, 2 patients showed small improvement, 1 patient without improvement • Group 2: 7/8 patients reported no improvement (median 3); 1 patient showed complete improvement (median 0) Cunha JM et al. Pharmacology 21: 175-185 (1980) Anticonvulsant effect of cannabidiol Methods • Controlled trial of 12 institutionalized, mentally handicapped patients with frequent seizures uncontrolled with conventional anticonvulsant therapy Intervention • Group 1: cannabidiol 300 mg daily for the first week then 200 mg daily for the next three weeks • Group 2: placebo Results • No statistically significant different in seizure frequency between the two groups • Mild drowsiness reported Ames, FR et al. South African Medical Journal 1985; 69:14 Double-blind clinical study of cannabidiol as a secondary anticonvulsant Methods • Randomized, controlled, cross-over trial of 12 patients with incompletely controlled epilepsy Intervention • Patients received: • Conventional antiepileptics for 3 months • Placebo for 6 months • Randomized to: • Cannabidiol 100 mg three times a day for 6 months then placebo for 6 months • Placebo for 6 months then cannabidiol 100 mg three times a day for 6 months Results • “no discernable effect” • “no effects on seizure pattern, character or frequency” Trembly. Marijuana ‘90 Internation Conference on Cannabis and Cannabinoids 1990. Christopher Campbell PGY2 Pediatric Pharmacy Resident Augusta University Medical Center University of Georgia College of Pharmacy [email protected] [email protected] Visit GPhAconvention.com/grow to download materials from this and other presentations.