Medical Marijuana. Medicalization of Marijuana. Objectives. Disclosure. Objectives. US FDA Drug Approval Process

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Ethelbert Hawkins
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1 Objectives Medicalization of Marijuana Joe Spillane Pharm.D., DABAT This is not about recreational marijuana. This is not about the Florida Governor election. This is not about politics at all.. This is not about anything but the medicalization of marijuana. 1 Disclosure Medical Marijuana I do not have 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 Review FDA process & medical marijuana Different cannabinoids: availability, legality Pharmacology and pharmacokinetics Safety and efficacy data Practical implications for Florida US FDA Drug Approval Process Preclinical testing Phase 1: safety healthy volunteers Phase 2: prelim efficacy/ safety patients Phase 3: efficacy/safety more patients 1

2 Phocomelia Thalidomide 2

Medical Marijuana http://azcapitoltimes.

co 16 Forward to the Past? Microbe Killer & Dr.

1937 Sulfanilamide Elixir Food Drug & Cosmetic Act Drug Safety

Efficacy 1983 Orphan Drug Act 2014 Medical Marijuana www.

3 Medical Marijuana Forward to the Past? Microbe Killer & Dr. Siblers Reanimating Solar Tincture 1906 Pure Food & Drug Act 1937 Sulfanilamide Elixir Food Drug & Cosmetic Act Drug Safety 1957 Thalidomide & Phocomelia Keefauer- Harris Act Drug Efficacy 1983 Orphan Drug Act 2014 Medical Marijuana hometestingblog.testcountry.com 18 3

Synthetic Cannabinoids Onset/Duration Onset=10mins after inhalation Variable duration Clinical presentation: Tachycardia, anxiety, psychomotor agitation Tremulousness, palpitations Reddened

Happy case report XLR-11 & UR-144 MMWR cases-16 with AKI-teens, sr cr=3-21mg/dl 5 required dialysis Clown Loyal, Phantom Wicked Dreams, Spice Gold Fatal toxicity 4 cases in Iowa 2013 (5F-PB-22)

4 Synthetic Cannabinoids Onset/Duration Onset=10mins after inhalation Variable duration Clinical presentation: Tachycardia, anxiety, psychomotor agitation Tremulousness, palpitations Reddened conjunctiva Increased appetite withdrawal Synthetic Cannabinoids Acute kidney Injury: Mr. Happy case report XLR-11 & UR-144 MMWR cases-16 with AKI-teens, sr cr=3-21mg/dl 5 required dialysis Clown Loyal, Phantom Wicked Dreams, Spice Gold Fatal toxicity 4 cases in Iowa 2013 (5F-PB-22) Clin Tox 2013;51: MMWR 2013;62(6): J Analyt Tox 2014;1-4. Synthetic Cannabinoids Manufacture/Sales Synthetic cannabinoids from Asia Sprayed on to herbal mixture dusting Internet sales not for human consumption Users: Teens and young adults Military Route of administration: smoked/inhaled ingested Different Smokes, Different Tokes Dronabinol (Marinol) Synthetic THC FDA approved in 1985 Chemo N&V AIDS wasting Onset= 30mins-1hr Peak effect=2-4hrs Duration=4-6hrs Prescription medication (CIII) 24 4

Different Smokes, Different Tokes Nabilone (Cesamet) Synthetic racemic mix THC/CBD FDA approved in 1985, marketed in 2006 Chemo N&V AIDS wasting 20% bioavail after 1 st pass effect 1mg capsules

25 Different Smokes, Different Tokes Other Cannabinoids Anandamide Rimonabant Tetrahydrocannabivirin Delta 8-THC Cannabinol Cannabichromene Cannabigerol Cannafattygetmehigh 28 Different Smokes,

5 Different Smokes, Different Tokes Nabilone (Cesamet) Synthetic racemic mix THC/CBD FDA approved in 1985, marketed in 2006 Chemo N&V AIDS wasting 20% bioavail after 1 st pass effect 1mg capsules Prescription medication (CII) Pharmacother 2013;33(2): Different Smokes, Different Tokes Other Cannabinoids Anandamide Rimonabant Tetrahydrocannabivirin Delta 8-THC Cannabinol Cannabichromene Cannabigerol Cannafattygetmehigh 28 Different Smokes, Different Tokes Nabiximols (Sativex) Oral mucosal liquid spray THC and CBD 2.7mg THC/spray 2.5mg CBD/spray Not yet FDA approved Neuropathic pain, spasticity Overactive bladder Derived from cannabis sativa plant Different Smokes, Different Tokes Cannabadiol (Epiodiolex) Inverse agonist Decreases psychotropic effects of THC Enhances anandamide effect Oral liquid form Not yet FDA approved(orphan drug) Lenox-Gestaut Syndrome Dravets Syndrome Pharmacother 2013;33(2):

Marijuana Pharmacokinetics Clinical Manifestations Oral: Bioavailability=5-20% (absorption-delayed/incomplete) Peak concentrations 1-3hrs,duration-5-8hrs Smoking: 50% of THC becomes smoke 50% of

6 Marijuana Pharmacokinetics Clinical Manifestations Oral: Bioavailability=5-20% (absorption-delayed/incomplete) Peak concentrations 1-3hrs,duration-5-8hrs Smoking: 50% of THC becomes smoke 50% of inhaled smoke is exhaled Estimated smoked bioavailability=10-25% Rapid absorption,pk-30mins,duration-2-3hrs VAPORIZATION Relaxation, sedation, decreased alertness Exaggerated mood & personality Analgesia Tachycardia Increased hunger Red eyes Coughing Marijuana Pharmacology Mechanism of Action: CB receptors & anandamide basal ganglia/cerebellum-motor act/coord hippocampus-short term memory limbic-reward system neocortex-thinking, hypothalamus-appetite 32 Use of Marijuana for Certain Medical Conditions Allows the medical use of marijuana for individuals with debilitating diseases as determined by a licensed Florida physician. Allows caregivers to assist patients medical use of marijuana. The Department of Health shall register and regulate centers that produce and distribute marijuana for medical purposes and shall issue identification cards to patients and caregivers. Applies only to Florida law. Does not authorize violations of federal law or any non-medical use, possession or production of marijuana. 35 Debilitating Diseases Cancer, AIDS/HIV+ Glaucoma Hepatitis C Crohn s disease ALS Parkinson s, Multiple Sclerosis

7 Medical Marijuana Efficacy Neurological Disorders Medical Marijuana Safety Spasiticity: effective/ probably effective Painful spasms: effective/ probably effective Urinary dysfunction: probably ineffective Tremor: probably ineffective Parkinsons: probably ineffective Epilepsy: unknown efficacy Smoked marijuana= unknown efficacy COMPARATIVE EFFICACY-unknown Neurology 2014;82: Addiction: 9% become addicted 17% of teens Cannabis withdrawal Mental Illness: w/ preexisting genetic vulnerability accelerates course of dz unproven causality NEJM 2014;370;23: J Am Acad Child Adolesc Psych 2012;51(7): Medical Marijuana Efficacy Pain Medical Marijuana Safety Brit J Clin Pharm: Excellent quality of trials Safe and mod effective Amer Acad Pain Medicine: 18 trial meta analysis Mod efficacy for chronic pain Short term trials/methodologic flaws Benefits offset by harms Pain Med 2009;10(8): Br J Pharmacol 2011;72(5): Cancer & Lung Disease: lower risk of lung cancer than w/tobacco increased risk of chronic bronchitis increase risk of resp. dz Motor Vehicle Accidents: increased THC blood levels=driver impairment +THC=3-7x incr risk of MVA EtOH & THC difficult to prevent DUIC--attitudes Clin Chem 2013;59(3): Medical Marijuana Efficacy Other Debilitating Conditions Medical Marijuana Adolescent Safety Glaucoma: lowers IOP, + testimonials Short duration q3-4hr dosing required=adr s Not recommended by Amer. Glaucoma Society Crohns Disease: some recent evidence Crohns & Colitis Foundation-research+, use now -neg AIDS wasting: probable efficacy Chemotherapy nausea/vomiting: probable efficacy Amer Glaucoma Society Position Statement Marijuana Jampel, Aug 10,2009 Pharmacol 2014;939(1-2): Risk perception and marijuana use Diversion to adolescents Increased risk of addiction School performance lower grades failure to reach educational goals memory impairment NEJM 2014; 370;23: Ann Epidemiology 2011;21:

Medical Marijuana Adolescent Safety Incr freq.

Iincreased impulsivity 43 NEJM 2014; 370;23:2219-2227.

Graders The adolescent brain is different from the

Volkow, Director NIDA 2013 Monitoring the Future

8 Medical Marijuana Adolescent Safety Incr freq. & earlier onset schizophrenia Decreased attention Iincreased impulsivity 43 NEJM 2014; 370;23: Monitoring the Future 2013 Lifetime Use-12 th Graders The adolescent brain is different from the adult brain --Dr. Volkow, Director NIDA 2013 Monitoring the Future Survey Florida Youth Substance Abuse 2013 Lifetime Use-12 th Graders 2013 Florida Youth Substance Abuse Survey 8

The Colorado Experience 2000: physicians can recommend mj to people suffering debilitating medical conditions Jan 2009: 5000 registered mj users Mar 2009: shift of federal policy Nov 2009: 30,000

smoking, abusing alcohol, or using drugs is virtually certain never to do so.

9 The Colorado Experience 2000: physicians can recommend mj to people suffering debilitating medical conditions Jan 2009: 5000 registered mj users Mar 2009: shift of federal policy Nov 2009: 30,000 registered mj users Oct 2011: 88,000 registered mj users J Am Acad Child Adolesc Psych 2012;51(7): Use of Marijuana for Certain Medical Conditions A child who reaches age 21 without smoking, abusing alcohol, or using drugs is virtually certain never to do so. --Joseph Califano, Chairman and President National Center on Addiction and Substance Abuse Columbia University Allows the medical use of marijuana for individuals with debilitating diseases as determined by a licensed Florida physician. Allows caregivers to assist patients medical use of marijuana. The Department of Health shall register and regulate centers that produce and distribute marijuana for medical purposes and shall issue identification cards to patients and caregivers. Applies only to Florida law. Does not authorize violations of federal law or any non-medical use, possession or production of marijuana. 53 The Colorado Experience Debilitating Medical Condition Cancer, AIDS/HIV+, Glaucoma Hepatitis C, ALS, Crohn s disease Parkinson s, Multiple Sclerosis ANY OTHER CONDITION FOR WHICH A PHYSICIAN BELIEVES THAT THE MEDICAL USE OF MARIJUANA WOULD LIKELY OUTWEIGH THE POTENTIAL HEALTH RISKS FOR A PATIENT. tiltingthescales.com

Debilitating Medical Condition ANY OTHER CONDITION FOR WHICH A PHYSICIAN BELIEVES THAT THE MEDICAL USE OF MARIJUANA WOULD LIKELY OUTWEIGH THE POTENTIAL HEALTH RISKS FOR A PATIENT.

Don t circumvent the US drug approval process Treat medicine like medicine!!!! 55 Marijuana is the ONLY Prescription Medication.

10 Debilitating Medical Condition ANY OTHER CONDITION FOR WHICH A PHYSICIAN BELIEVES THAT THE MEDICAL USE OF MARIJUANA WOULD LIKELY OUTWEIGH THE POTENTIAL HEALTH RISKS FOR A PATIENT. How to Really Medicalize Marijuana Allow, advocate, and expedite research Ensure access to research medications Provide reasonable dosing/routes of admin. Don t circumvent the US drug approval process Treat medicine like medicine!!!! 55 Marijuana is the ONLY Prescription Medication. to be approved by popular opinion to be approved for use without scientific scrutiny to be smoked to have no standardized dose, concen, composition to be recommended not prescribed to require no monitoring (no interxns, no SE s) to require no counseling or education 56 Marijuana is the ONLY Prescription Medication. to have its own distribution system (separate and distinct from pharmacy) for which a recall would be essentially impossible with immunity for physicians with immunity for caregivers with no training required for caregivers with immunity for producers and distributors to require a Florida constitutional amendment 57 10

Marijuana and Adolescents: Truth and Consequences. Disclosure Statement OBJECTIVES. Secondary Objectives. State of Marijuana in US

Marijuana and Adolescents: Truth and Consequences Clinical Advances in Pediatrics Symposium Children s Mercy Park September 28, 2017 Disclosure Statement I have no actual or potential conflict of interest