Medical Cannabis Audrey Umbreit, PharmD, BCACP MAPA Pharmacology Conference May 11, 2018

Learning Objectives

• Identify approved medical uses of cannabis in Minnesota • Review the endo-cannabinoid system and pharmacology of CBD and THC • Discuss current evidence regarding safety and efficacy of medical cannabis • Create a monitoring plan for a patient using medical cannabis

Legalization is Growing

National Conference of State Legislatures www.ncsl.org Accessed 11/14/16 Growth of Medical Cannabis in MN

Intractable pain added as qualifying diagnosis

Minnesota Department of health. Medical Cannabis Program Update April 2018.

Approved medical uses in MN

• Cancer (must be • Severe and persistent accompained by muscle spasms severe or chronic pain, (including MS) nausea or severe • Terminal illness with wasting life-expectancy of less • Glaucoma than 1 year • HIV/AIDS • Inflammatory Bowel • Tourette Syndrome Disease (including • ALS Crohn’s Disease) • • Seizures (including Intractable Pain – epilepsy) added in 2016 • PTSD – added in 2017

Minnesota Department of health. Medical Cannabis Program Update October 2016. New Approved Uses 2018

• Autism • Obstructive Sleep Apnea • Patients can enroll July 1, 2018 • Pick up medication August 1, 2018 ENDO-CANNABINOID SYSTEM Components of endocannabinoid system • Cannabinoid Receptors • CB1 = suppresses neurotransmitter release in CNS (5-HTP, glutamate, acetylcholine, GABA, noradrenaline, dopamine) • CB2 = inhibits cytokine release in immune cells • Endogenous ligands • Anandamide (AEA) • 2-arachidonoylglycerol (2-AG)

Health Canada. Information for health care professionals. Cannabis and the cannabinoids. February 2013. Distribution of CB1 and CB2

• CB1 (green): • Brain – cortex, caudate nucleus, basal ganglia, hypothalamus, cerebelum, hippocampus, amygdala, spinal cord • Lungs • Vascular system • Muscles • GI tract • Reproductive organs • CB2 (yellow) • Spleen • Bones • Skin • Brain – glial cells • CB1 & CB2 (blue) • Immune system • Liver • Bone Marrow • Pancreas • Brainstem

Endocannabinoid system. http://www.fundacion-canna.es/en/endocannabinoid-system. Accessed 12/2/16. Phytocannabinoids found in cannabis

Psychoactive Non-psychoactive • Delta-9-tetrahydrocannabinol • Cannabidiol (CBD) (THC) • Partial agonist at CB-1 and CB-2 • Does not bind to either CB- • Activity at non-CB receptors 1 or CB-2 • Responsible for psychoactive effects (CB-1 activity in CNS) • Activity at other targets • Cannabinol (CBN) • No psychoactive effects • Product of THC oxidation • 10% of the activity of THC • Tetrahydrocannabivarin • Cannabigerol (CBG) (TCHV) • Partial agonist at CB-1 and CB2 • CB-1 antagonist • May also block 5-HT1A (serotonin) receptors • CB2 partial agonist • a2 adrenoreceptor agonist

Health Canada. Information for health care professionals. Cannabis and the cannabinoids. February 2013. Pharmacologic activities of cannabis : Therapeutic effects

Body System Effects Central Nervous system Analgesia (modest effect), Euphoria, Anti-emetic, Appetite stimulation Cardiovascular system Vasodilation, Increased cardiac output, GI system Anti-inflammatory actions Musculoskeletal system Attenuates muscle spasticity in MS Eye Lowers intraocular pressure Immune system Immunomodulatory effects

Health Canada. Information for health care professionals. Cannabis and the cannabinoids. February 2013. Pharmacologic activities of cannabis: Adverse effects Body System Effects CNS Dysphoria, anxiety, psychosis, CNS depression, drowsiness, memory impairment, incoordination, hyper- emetic (with chronic use), weight gain, tolerance (with chronic use), dependence (with chronic use) Cardiovascular system Tachycardia, atrial fibrillation, ventricular arrhythmia, increased risk for MI, increased risk for stroke Respiratory system Carcinogenesis, increased inflammation in lungs GI system Decreased motility, increased risk of hepatic steatosis/fibrosis Musculoskeletal system May negatively impact bone healing Reproductive system (male) Anti-androgeneic, decreased sperm count and motility Reproductive system (female) Menstrual cycle changes, ovulation suppression

Health Canada. Information for health care professionals. Cannabis and the cannabinoids. February 2013. Prescription drugs affecting endocannabinoid system • Dronabinol (Marinol) • Indications: • Appetite stimulation in AIDS • Chemotherapy-induced nausea and vomiting • Synthetic THC with equal affinity to both CB1 and CB2 receptors • Nabilone (Cesamet) • Indication: Chemotherapy-induced nausea and vomiting • Synthetic THC analogue • Nabiximols (Sativex) • Approved in Canada, not in USA • Indication: Spasticity in MS • Botanical extract from cannabis strains

Micromedex. 2016. Cannabis products available in Minnesota • Minnesota Medical Solutions

• Leafline Labs

Cannabis: Is there any evidence? Evidence: Summary

• Overall, weak evidence • Few, small trials • Many poorly designed • At least some evidence for all approved uses in MN

Evidence for approved uses

Cancer Pain, Nausea/Vomiting, Cachexia/wasting • Combo of THC and CBD may be more effective than THC alone for pain • Doses >25mg/day poorly tolerated • Pooled analysis of 2/3 trials in US with nabiximols (THC/CBD) failed to meet primary endpoint • Solid data for dronabinol (THC) for CINV; less so for cachexia/wasting • Older data from plant-derived THC showed positive effects for cachexia/wasting Glaucoma • CBD not effective in lowering intraocular pressure • Low doses (5mg) of THC reduces IOP for 4-5 hours • Larger doses (20-25mg) THC reduces IOP for 10 hours, but increase in intolerable side effects

HIV/AIDS • Solid data for dronabinol (THC) in improving appetite and weight

MN Dept of Health. Review of medical cannabis studies relating to chemical compositions and dosages for qualifying medical conditions. July 2016. Evidence for approved uses

Tourette syndrome •2 small studies of oral, plant-derived THC •Doses of 2.5mg – 10mg per day •Modest reduction in symptoms; 1/3 patients discontinued due to side effects

ALS •2 small trials of dronabinol 2.5mg – 10mg per day •Little evidence of effectiveness •Doses well tolerated

Muscle Spasms •Mostly MS patients •THC with or without CBD •Slow titration over weeks vs. days reduces severity of side effects •THC may be more effective at higher doses; better tolerated when given with CBD

MN Dept of Health. Review of medical cannabis studies relating to chemical compositions and dosages for qualifying medical conditions. July 2016. Evidence for approved uses

Crohn’s disease • 2 trials with mostly CBD (THC:CBD ratio of 1:10 and CBD monotherapy) • Trial results have not yet been reported

Seizures • 4 trials - See additional slides

Intractable pain • 4 trials (mostly neuropathic pain) -See additional slides

MN Dept of Health. Review of medical cannabis studies relating to chemical compositions and dosages for qualifying medical conditions. July 2016. Evidence for approved uses

PTSD

•A single Double-blind randomized crossover trial, n=10, compared nabilone (a pharmaceutical cannabinoid) 0.5mg titrated to daily max of 3mg versus placebo x 7 weeks •Nightmares, global clinical state and general well-being were self-reported and improved with nabilone group; no effect on sleep quality and quantity

Autsim Spectrum Disorder •Animal studies show promise •2 ongoing DBRPCTs are registered with www.clinicaltrials.gov Anticipated completion dates of 2019 and 2021 •Single case study of 6y/o child using dronabinol 1 drop (0.62mg THC) daily, with gradually increasing doses to the max tolerated dose of 3.62mg THC per day (2 drops in AM, 1 drop at midday, 3 drops in PM) x 6 months •Symptom severity decreased in 5 categories: hyperactivity, lethargy, irritability, stereotypic behavior and inappropriate speech.

Obstructive Sleep Apnea •N=22 compared dronabinol (max dose of 10mg daily) with placebo on sleep apnea/hypopnea index at 3 weeks showed statistical significance in favor of dronabinol

U.S. National Academis of Sciences, Engineering and Medicine. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. 2017. MN Dept of Health. Autism Spectrum Disorder. Issue Brief. 09/2017. Cannabis Trials: Seizures Trial Date N Description Outcomes Toward drugs 1978 9 RPCT, DB 2/4 pts on CBD were derived from 200mg CBD daily vs. completely seizure free cannabis placebo x 3 months 0/5 pts on placebo had improvement Chronic admin of 1980 15 RPCT, DB Improvement in patient CBD to health 200-300mg CBD self-reported seizure volunteers and orally vs. placebo x 8- activity epileptic pts 18 weeks Anticonvulsant 1986 12 RPCT No difference in seizure effect of 300mg CBD orally vs. frequency cannabidiol. placebo x 3 weeks CBD in patients 2015 214 Open-label 36.5% reduction in motor with treatment- Epidiolex (99% CBD in seizures resistant epilepsy sesame oil) titrated up to max of 50mg/kg/day x 12 weeks

MN Dept of Health. Review of medical cannabis studies relating to chemical compositions and dosages for qualifying medical conditions. July 2016. Cannabis Trials: Intractable pain Trial Date N Description Outcomes Efficacy of two 2004 48 RPCT, DB, Crossover 30% decrease in pain cannabis based Oral spray 1:1 score medicinal THC:CBD vs THC alone NNT = 9 (1:1 spray) extracts… vs. placebo x 2 weeks NNT = 7.7 (THC only) Sativex treats 2007 125 RPCT, DB NNT = 8.5 for 50% neuropathic pain Sativex spray vs reduction in pain score placebo x 5 weeks NNT= 8.6 for 30% reduction THC/CBD spray in 2013 339 RPCT, DB No statistical difference combo with Pts also had MS in end point of pain existing treatment THC/CBD spray vs. inventory placebo x 14 weeks Long-term 2015 234 Open-label 30% decrease in pain maintenance of 9-months score in 60% of patients effect of THC/CBD 23% pts stopped spray… treatment due to ADE

MN Dept of Health. Review of medical cannabis studies relating to chemical compositions and dosages for qualifying medical conditions. July 2016. Neuropathic pain

Change in pain scale

MN Dept of Health. Medical cannabis for non-cancer pain: A systemic review. http://www.health.state.mn.us/topics/cannabis/intractable/medicalcannabisreport.pdf APPLYING TO PRACTICE Monitoring your patient on cannabis • Drug interactions • Pregnancy / Lactation • Impact on other health conditions Cannabis Drug Interactions

• THC Metabolism • Substrate of CYP 2C9, 2C19, 3A4 • Inhibits CYP 3A4, 3A5, 2C9 and 2C19 (in vitro) • CBD Metabolism • Inhibits CYP 2C19, 3A4, 3A5 (in vitro) • Inhibits metabolites of THC formed by CYP 3A4 • Cannabis smoke • Polyaromatic hydrocarbons Induces CYP 1A2 • THC, CBD Inhibits CYP 1A1, 1A2 and 1B1

Cannabis Drug Interactions

Interaction Description CNS depressants – sedatives, alcohol Increased risk for CNS depression Other forms of cannabis Taking more than one form of cannabinoids, prescription or recreational, increases risk for overdose Inhibitors of 2C9, 2C19 and 3A4 (ie, Decreases metabolism of THC and fluoxetine, nefazodone, omeprazole, increases risk for adverse effects erythromycin, diltiazem, ritonavir, amiodarone Substrates of 1A1, 1A2, 1B1 (ie, THC and CBD inhibit these enzymes amitriptyline, theophylline) and may increase the risk for adverse effects from the substrates Opioids Cannabis may decrease efficacy of some opioids (ER Morphine) and may increase euphoria Health Canada. Information for health care professionals. Cannabis and the cannabinoids. February 2013. Pregnancy and Lactation

• Effect on fertility • Decreases sperm count and motility in men • May suppress ovulation in women • Risks during pregnancy • Increased risk for miscarriage • Long-term developmental problems • Lactation • Cannabinoids excreted in breast milk

Health Canada. Information for health care professionals. Cannabis and the cannabinoids. February 2013. Patient Case: MJ

• 38 y/o female intractable pain due to fibromyalgia • Recently enrolled in medical cannabis program • Taking vaporization solution with 10:1 ratio of THC:CBD • Reports no adverse effects so far • Presents to clinic today for regular check up • PMH: fibromyalgia, depression, hypertension • Current medications include: • Amitriptyline 25mg at bedtime • Amlodipine 5mg daily • Duloxetine 60mg daily • Oxycodone/acetaminophen 5/325 1 tablet four times a day as needed • Vitamin D 1000 IU daily

What would you do?

• Drug interactions • Amitriptyline • Opioids • Labs / Measures to check • BP • PHQ-9 What if…

• MJ complaining of constipation? - Result of amitriptyline – cannabis interaction?

• MJ has BP of 96/60? -Vasodilation side effect of cannabis?

• PHQ-9 is 23 today (3 months ago, it was 6)? -Adverse effect of THC content?

• MJ wants to become pregnant? Discussion / Questions?