Disclosure Objectives

4/3/2019

Disclosure

Kevin Schleich reports no actual or potential conflicts of interest associated with this presentation.

www.google.com/images_cheech&chong

Objectives • Review historical context of medical cannabis and literature that addresses efficacy of cannabis for multiple medical conditions

• Discuss safety concerns from both an acute and chronic use standpoint

• Compare and contrast available formulations of medical cannabis in Iowa

• Highlight the process by which patients in Iowa can receive medical cannabis

• Summarize the Department of Family Medicine’s (DFM) policy on medical cannabis

1 4/3/2019

Weed 101

• Marijuana contains numerous extractable substances – Steroidal components – Volatile compounds

• 60 cannabinoids can be isolated – Delta‐9‐tetrahydrocannabinal (THC): main psychoactive cannabinoid • Dronabinol (Marinol®) – Cannabidiol (CBD): main non‐psychoactive cannabinoid • Agents non FDA‐approved in US, but currently investigational (Nabiximol®, Sativex®, Epidiolex®)

Herman, Ronald A. (2018). Current Iowa Medical Cannabis Regulations.

Weed 101

• Two main cannabinoid receptors throughout the human body

– CB1: brain, spinal cord, some periphery – CB2: intestinal tract, peripheral organs, immune system

• Neither CBD or THC directly agonize

either the CB1 or CB2 receptor – THC a partial agonist of CB1 – CBD influences endogenous cannabinoids

Herman, Ronald A. (2018). Current Iowa Medical Cannabis Regulations.. http://sensipharma.com/ecs

Weed 101

• CBD antagonizes the effects of THC at the

CB1 receptor THC THC + CBD

• CBD + THC CBD – Pain relief – Anti‐spasmodic

• CBD only – Epilepsy

Herman, Ronald A. (2018). Current Iowa Medical Cannabis Regulations. www.analyticalcannabis.com

2 4/3/2019

Iowa Qualifying Conditions • Cancer, AIDS/HIV, or any terminal illness if: – Severe/chronic pain – Nausea/severe vomiting – Cachexia or severe wasting

• Neuromuscular disorders: – Multiple sclerosis (with severe/persistent muscle spasms) – Amyotrophic lateral sclerosis (Lou Gehrig’s Disease) – Parkinson’s disease

• Seizures (including those characteristic of epilepsy)

• Crohn’s disease

• Untreatable pain – “…any pain whose cause cannot be removed… the full range of pain management modalities have been used without adequate result” – accounts for ~90% of clientele in legal states

Does the Stuff Work?

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Efficacy Data

• The National Academies of Sciences, Engineering, and Medicine (NASEM) – “The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research”

– Comprehensive report highlighting the health effects of recreational/therapeutic cannabis use

– Published in 2017

http://www.nationalacademies.org/hmd/Reports/2017/health‐effects‐of‐cannabis‐and‐cannabinoids.aspx

3 4/3/2019

Efficacy Data • Chronic Pain – “…there is substantial evidence that cannabis is an effective treatment for chronic pain in adults”

– NASEM cites 5 systematic reviews (n=2454) • Low‐quality evidence • 2 studies focused on fibromyalgia • Pain scores decreased by ~30% on average

– Generally, higher THC content = greater pain relief

– 31 active trials on clinicaltrials.gov

Herman, Ronald A. (2018). Current Iowa Medical Cannabis Regulations. http://www.nationalacademies.org/hmd/Reports/2017/health‐effects‐of‐cannabis‐and‐cannabinoids.aspx www.clinicaltrials.gov

Efficacy Data • Cancer‐Associated Symptoms – Dronabinol and nabilone approved in 1985 for nausea/vomiting (n/v) associated with chemotherapy

– “…conclusive evidence that oral cannabinoids are effective antiemetics…” • Dronabinol = ondansetron for delayed n/v • No evidence that combined CBD:THC products are effective

– “…insufficient evidence to support or refute the use of cannabinoids for cancer‐associated anorexia‐cachexia • Limited evidence that cannabinoids can be useful for HIV/AIDS‐related anorexia and weight loss

• Very little primary literature evaluating CBD:THC combinations

Efficacy Data • Seizure Management – “… no or insufficient evidence to support or refute that cannabis or cannabinoids are effective for seizure management”

– NASEM cites 2 systematic reviews (n<50) • Small numbers of patients • Low quality evidence

– Further case series have been published demonstrating 25‐100% reduction in seizure frequency • 3 current trials active on clinicaltrials.gov

– Most studies used only CBD

4 4/3/2019

Efficacy Data • Multiple Sclerosis (MS) Spasticity – “…substantial evidence that oral cannabinoids are an effective treatment for improving patient‐reported MS spasticity symptoms”

– “… limited evidence for an effect on clinician‐ measured spasticity”

– NASEM cites 2 systematic reviews (n=2138) • Reduction (non‐statistically significant) in Ashworth score for spasticity

• Balanced 1:1 ratio of THC/CBD products predominantly used

– 2 active trials on clinicaltrials.gov

Efficacy Data • Parkinsonism – “…insufficient evidence that cannabinoids are an effective treatment for the motor system symptoms associated with Parkinson’s disease or the levodopa‐ induced dyskinesias”

– NASEM cites 1 systematic review (n=26)

– Randomized‐controlled trial completed since NASEM publications suggests improvement in quality of life and motor symptoms (n=21) • CBD alone was main ingredient studied

– 4 active trials on clinicaltrials.gov

Efficacy Data • Irritable Bowel Syndrome (IBS) – “… insufficient evidence to support or refute that cannabis is an effective treatment for IBS”

– NASEM cites only 1 relevant trial (n=36) • No effect of dronabinol on GI transit

– Trial evaluated by NASEM only utilized synthetic cannabinoid, dronabinol

– Some trials have demonstrated symptom improvement • No evidence of anti‐inflammatory effect

– 1 active trial on clinicaltrials.gov

http://www.nationalacademies.org/hmd/Reports/2017/health‐effects‐of‐cannabis‐and‐cannabinoids.aspx Gastroenterol Hepatol (N Y). 2016 Nov; 12(11): 668–679

5 4/3/2019

Efficacy Data • NASEM addresses efficacy for indications not approved in the state of Iowa

Indication Efficacy Statement “…limited evidence that cannabinoids are effective for improving Anxiety situational anxiety symptoms” “…moderate evidence that cannabinoids are effective for Sleep disturbances improving short‐term sleep outcomes in those with obstructive sleep apnea, fibromyalgia, chronic pain, and MS” “…limited evidence that cannabinoids are ineffective for improving Dementia symptoms” “…limited evidence that cannabinoids are ineffective for reducing Depression depressive symptoms” Post‐traumatic stress “…there is no evidence to support or refute an association disorder (PTSD) between cannabis use and development of PTSD

Herman, Ronald A. (2018). Current Iowa Medical Cannabis Regulations. http://www.nationalacademies.org/hmd/Reports/2017/health‐effects‐of‐cannabis‐and‐cannabinoids.aspx

Condition Efficacy Studied Product(s)

Chronic Pain 1:1 CBD/THC*

Cancer/HIV‐Related Symptoms THC (Dronabinol)

Seizures CBD

MS Spasticity Symptoms 1:1 CBD/THC

Parkinson’s CBD

Irritable Bowel Synthetic cannabinoids

Situational Anxiety CBD

Sleep Disturbances Semi‐synthetic cannabinoids

Dementia Semi‐synthetic cannabinoids

Depression Semi‐synthetic cannabinoids

PTSD Variety

* Higher doses of THC = greater pain control Herman, Ronald A. (2018). Current Iowa Medical Cannabis Regulations. http://www.nationalacademies.org/hmd/Reports/2017/health‐effects‐of‐cannabis‐and‐cannabinoids.aspx

www.google.com/images

6 4/3/2019

Short‐Term Adverse Effects • Marijuana  inhalation/ingestion Impaired motor coordination Short-term memory Paranoia/psychosis impairment Dry mouth

Tachycardia Hypertension

Nausea/ vomiting

www.google.com/images N Engl J Med. 2014;371(9):879

Long‐Term Adverse Effects

Addiction* Altered brain • 9%: overall development* • 17%: begin as adolescent • 25‐50%: daily user Worsening educational Cognitive outcomes* impairment*

Diminished life Increased risk of satisfaction* chronic psychosis disordersΩ

* = effect strongly Ω = in those with a associated with initial use predisposition to such in adolescence disorders

Adverse Effects in Studies

CBD Solution Children With Epilepsy (n=213) > 10% 5‐10% < 5% Somnolence (21%) Increased appetite (7%) Sedation (3%) Fatigue (17%) Weight gain (6%) Decreased appetite (15%) Weight loss (5%) Diarrhea (14%) Convulsions (5%) Gait disturbance (5%)

Devinsky, Orrin. 2015,. “Epidiolex (Cannabidiol) in Treatment Resistant Epilepsy”. Washington, DC. www.google.com/images

7 4/3/2019

“Pharmacy stuff… pharmacy stuff… pharmacy stuff… pharmacy stuff… pharmacy stuff”

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Pharmacokinetics

Sublingual Trans‐ Inhaled Oral /Buccal cutaneous Onset Seconds 5‐15 min ? 60 min Time to Peak 30 min 4 hours ? 4‐6 hours Duration 2‐4 hours ? ? > 8 hours

Absorption < inhaled 10‐35% CBD > THC ~5% Bioavailability > oral • Distributes readily into well‐vascularized organs (lung, heart, brain, liver) Distribution • Chronic use  accumulates in adipose tissue • THC highly lipophilic  crosses placenta; excreted into breast milk Metabolism THC  CYP2C9, CYP3A4  Active CBD  CYP2C19, CYP3A4  (by CYP enzymes) metabolite (2x as potent) Inactive metabolite Route of Elimination Half‐Life THC: 22 hours Excretion Feces: 70% (5% unchanged) CBD, occasional use: 24‐31 hours Urine: 30% CBD, frequent use: 2‐5 days

Ku, Jennifer. (2018). Cannabis Can Do What? Pharmacological Considerations with Cannabinoids.

Drug‐Drug Interactions

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8 4/3/2019

What Effects Cannabis

Increase Cannabinoid Decrease Cannabinoid Levels Levels

• Grapefruit • Rifampin • Azole antifungals • Carbamazepine • Clarithromycin • St. John’s Wort • Amiodarone • Barbiturates • HIV Antivirals

• Common offenders for drug‐drug interactions when utilizing the CYP enzyme system

• Current manufacturers recommend monitoring efficacy and safety if administering concurrently with above drugs • No preemptive dose adjustments necessary

Ku, Jennifer. (2018). Cannabis Can Do What? Pharmacological Considerations with Cannabinoids.

What Cannabis Effects Cannabis Induces Cannabis Inhibits CYP2C8, CYP2C9, CYP2C19, UGT1A9, Enzymes CYP1A2, CYP2B6 UGT2B7 Decreases efficacy of the following Increases efficacy of the following Effect drugs drugs Neuro/psych: • Citalopram Neuro/psych: • Diazepam • Duloxetine • Lamotrigine • Haloperidol • Lorazepam • Olanzapine Platelet inhibitors: Musculoskeletal/analgesia: • Clopidogrel • Cyclobenzaprine Drugs Musculoskeletal/analgesia: • Naproxen • NSAIDS • Tizanidine Lipid‐lowering: Opioids: • Fibrates • Methadone Anti‐hyperglycemic: Hormones: • Sulfonylureas • Estradiol Opioids: • Morphine

Ku, Jennifer. (2018). Cannabis Can Do What? Pharmacological Considerations with Cannabinoids.

www.google.com/images

9 4/3/2019

Products in Iowa

20:1 2:1 1:1 1:20 (CBD:THC) (CBD:THC) (CBD:THC) (CBD:THC)

5 mg:5 mg 0.25 mg:5 mg Capsule 20 mg:1 mg 0.5 mg:10 mg 10 mg:10 mg 1 mg:20 mg 5 mg:0.25 mg/0.25 mL Tincture ~5 mg:5 mg/0.25 mL 0.25 mg:5 mg/0.25 mL 25 mg:2 mg/0.25 mL 17.5 mg:8.75 mg/0.5 tsp* Cream 17.5 mg:8.75 mg/0.5 tspΩ pediatric formulation; * = no scent; Ω = rosemary extract scent

www.medpharmiowa.com/products www.google.com/images

What’s In Recreational?

Product Weight/Size THC (mg) Pretzels 0.18 oz (5 g) 3 Honey 1 tsp: 0.2 oz (7 g) 8 Cookie 0.56 oz (16 g) 10 Gummy Bear 0.09 oz (2.5 g) 25 Green Tea 0.07 oz (1.9 g) 40 Chocolate Bar 1.5 oz (43 g) 200 Brownie 3.5 oz (100 g) 250

www.latimes.com/projects/la‐me‐weed‐101‐1hc‐calculator/ www.google.com/images

Can I Afford This? • Insurance does not cover – Cash only form of payment accepted (debit coming) – Credit card not permitted due to “federal regulations”

• Price of all products published on MedPharm website

• Cost obviously varies widely based on dose utilized/product

www.medpharmiowa.com/products www.google.com/images

10 4/3/2019

20:1 2:1 1:1 1:20 (CBD:THC) (CBD:THC) (CBD:THC) (CBD:THC)

$49.99/30 caps $33.99/30 caps Capsule $69.99/30 caps $64.99/30 caps $94.99/30 caps $119.99/30 caps $27.99/14 mL Tincture $89.99/14 mL $79.99/14 mL $129.99/14 mL $79.99/56 g Cream $79.99/56 g

www.medpharmiowa.com/products www.google.com/images

Cost Example

• 4 kg infant requiring low THC formulation of tincture for seizures – 5 mg CBD:0.25 mg THC/0.25 mL

– 80‐160 mg total CBD/day in a divided dose

– 60 mg twice daily (120 mg/day = right in the middle)

– 3 mL twice daily = 6 mL/day = 180 mL/month

– 13 bottles of tincture would provide 182 mL

– 13 bottles x $27.99/bottle = $365/month

Herman, Ronald A. (2018). Current Iowa Medical Cannabis Regulations

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11 4/3/2019

Prescribing Review

Amoxicillin 500 mg Take 2 caps 3 times daily x 10 days

#600 refills

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“Authorizing” Review

You have a condition

Dr. XYZ

My high school degree and 2- week training course leads me to believe your child needs this dose of cannabis.

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Application/Registration

• Patients submit a three‐page application to the Iowa Department of Public Health (IDPH) to receive a medical cannabidiol registration card – Available online at IDPH website – $100 non‐refundable application fee – $25 non‐refundable reduced application fee for low‐income

• Patient must be > 18 years of age

• Application must have physician (not PA or ARNP) signed attestation

12 4/3/2019

Application/Registration • MD Attestation Requirements (page 3) – Established patient‐provider relationship with the patient

– Currently the primary care provider of the patient

– Confirmation that the patient suffers from a qualifying condition

– Have counseled patient (including guided patient to IDPH website) about benefits/risks of medical cannabidiol

– Agree to annually evaluate continuing need

Application/Registration • Patient obtains registration card from the Iowa Department of Transportation (DOT)

• As of December 1, 2018, dispensaries were allowed to begin the sale of medical cannabis

Waterloo Sioux City

Davenport

Council Windsor Bluffs Heights www.idph.iowa.gov/cbd/Program‐Data‐and‐Statistics

Iowa Cannabis Statistics (3/25/19)

# of People # of People # of People # of People # of People Role in Registry (11/16/18) (11/30/18) (1/11/19) (2/1/19) (3/25/19) Issued Cards: # patients with active, DOT‐issued 499 663 1197 1361 2170 cards Healthcare Practitioners: unique # of physicians who 325 353 463 505 619 have certified patients

www.idph.iowa.gov/cbd/Program‐Data‐and‐Statistics

13 4/3/2019

Iowa Cannabis Statistics

11/30/193/25/192/1/19

“pain”= 65% “pain”= 61% “pain”= 67%

www.idph.iowa.gov/cbd/Program‐Data‐and‐Statistics

Iowa Legislation House Study Bill 244 • Advanced in Iowa House of Representatives (March 2019)

• Proposed changes to current medical cannabis law: – Lifting the 3% THC cap on available products (20 g/90 days)

– Allow physician assistants (PAs) and advanced registered nurse practitioners to sign attestation papers (ARNPs)

– Dispensaries may employ a pharmacist or pharmacy technician

– Removes prohibition on certain felons from applying for registration card

https://www.legis.iowa.gov/legislation/BillBook?ga=88&ba=HSB244 www.google.com/schoolhouserock

UIHC Department of Family Medicine (DFM)Policy 1. Licensed physicians in the State of Iowa are able to provide attestation cards to potential legal users of medical cannabis

2. Legal users must have the cards to apply to the Department of Public Health for a medical cannabis registration card

3. All University of Iowa Department of Family Medicine physicians will not provide attestation cards until January 1, 2020 – UI QuickCare PA/ARNP cannot provide attestation cards under current law

4. When declining to fill out the registration form, we should not actively assist in finding another physician or physician group who will fill out the attestation form

5. The January 1, 2020 date is the earliest date this will be considered. This date could be extended pending utilization patterns and distribution complications

14 4/3/2019

DFM Policy Explanation “Medical cannabis contains minimal amounts of the kind of marijuana that is used for recreational uses, delta‐9‐tetrahydrocannabinol(THC). The kind of marijuana that dispensaries would provide contains both cannabidiol (CBD) and THC. The CBD portion may have some scientific effect on your condition, but opposes the effect of THC. The THC portion is what provides the “high” effect in recreational marijuana, and the amount in medical cannabis is very small, and will be very expensive.

Because of the relative unknowns, cost, and concern for patient safety, our practice has decided to wait for more information until we consider completing your application.”

DFM Policy Rationale • Policy decision is not based on the lack or presence of legitimate scientific evidence, but instead suggests there is sufficient uncertainty about multiple aspects of prescribing, producing, and dispensing medical cannabis that warrants a watchful waiting approach by our practice

www.google.com/images

Review • Marijuana contains hundreds of substances, including CBD and THC which have been produced for medical use

• Medical cannabis was able to be distributed to patients as of December 1, 2018

• While efficacy data is present for some indications of medical cannabis, it is lacking for other indications

• Like any substance, medical cannabis does have adverse effects that must be considered

• UIHC DFM will reevaluate the policy of providing attestation for medical cannabis in January 2020

15 4/3/2019

Questions? Questions?