Schleich, Kevin - Cannabinoids- Pharmacology, Medical ... · • Marijuana contains numerous extractable substances –Steroidal components –Volatile compounds • 60 cannabinoids

4/3/2019

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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

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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

• CBD + THC

– Pain relief

– Anti‐spasmodic

• CBD only

– Epilepsy

www.analyticalcannabis.com

THC

CBD

THC + CBD

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

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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?

www.google.com/images

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

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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.aspxwww.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


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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



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



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.aspxGastroenterol Hepatol (N Y). 2016 Nov; 12(11): 668–679

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Efficacy Data• NASEM addresses efficacy for indications notapproved in the state of Iowa

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

Indication Efficacy Statement

Anxiety“…limited evidence that cannabinoids are effective for improving

situational anxiety symptoms”

Sleep disturbances“…moderate evidence that cannabinoids are effective for

improving short‐term sleep outcomes in those with obstructive sleep apnea, fibromyalgia, chronic pain, and MS”

Dementia“…limited evidence that cannabinoids are ineffective for improving

symptoms”

Depression“…limited evidence that cannabinoids are ineffective for reducing

depressive symptoms”

Post‐traumatic stress disorder (PTSD)

“…there is no evidence to support or refute an association between cannabis use and development of PTSD

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


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Short‐Term Adverse Effects

• Marijuana inhalation/ingestion

Dry mouth

Nausea/ vomiting

Tachycardia

Hypertension

Short-term memory

impairment

Impaired motor coordination

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

Paranoia/psychosis

Long‐Term Adverse Effects

Addiction*• 9%: overall• 17%: begin as adolescent• 25‐50%: daily user

Altered brain development*

Worsening educational outcomes*Cognitive

impairment*

Increased risk of chronic psychosis

disordersΩ

Diminished life satisfaction*

Ω = in those with a predisposition to such

disorders

* = effect strongly associated with initial use

in adolescence

Adverse Effects in Studies

CBD Solution Children With Epilepsy(n=213)

> 10% 5‐10% < 5%

Somnolence (21%)Fatigue (17%)

Decreased appetite (15%)Diarrhea (14%)

Increased appetite (7%)Weight gain (6%)Weight loss (5%)Convulsions (5%)

Gait disturbance (5%)

Sedation (3%)

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

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“Pharmacy stuff… pharmacy stuff… pharmacy stuff…

pharmacy stuff… pharmacy stuff”


Pharmacokinetics

InhaledSublingual /Buccal

Trans‐cutaneous

Oral

Absorption

Onset Seconds 5‐15 min ? 60 min

Time to Peak 30 min 4 hours ? 4‐6 hours

Duration 2‐4 hours ? ? > 8 hours

Bioavailability 10‐35%< inhaled> oral

CBD > THC ~5%

Distribution• Distributes readily into well‐vascularized organs (lung, heart, brain, liver)• Chronic use accumulates in adipose tissue• THC highly lipophilic crosses placenta; excreted into breast milk

Metabolism(by CYP enzymes)

THC CYP2C9, CYP3A4 Activemetabolite (2x as potent)

CBD CYP2C19, CYP3A4 Inactive metabolite

Excretion

Route of Elimination Half‐Life

Feces: 70% (5% unchanged)Urine: 30%

THC: 22 hoursCBD, occasional use: 24‐31 hours

CBD, frequent use: 2‐5 days

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

Drug‐Drug Interactions


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What Effects CannabisIncrease Cannabinoid

Levels

• Grapefruit

• Azole antifungals

• Clarithromycin

• Amiodarone

• HIV Antivirals


Decrease Cannabinoid Levels

• Rifampin

• Carbamazepine

• St. John’s Wort

• Barbiturates

• 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

What Cannabis Effects


Cannabis Induces Cannabis Inhibits

Enzymes CYP1A2, CYP2B6CYP2C8, CYP2C9, CYP2C19, UGT1A9,

UGT2B7

EffectDecreases efficacy of the following

drugsIncreases efficacy of the following

drugs

Drugs

Neuro/psych:• Duloxetine• Haloperidol• Olanzapine

Musculoskeletal/analgesia:• Cyclobenzaprine• Naproxen• Tizanidine

Opioids:• Methadone

Hormones:• Estradiol

Neuro/psych:• Citalopram• Diazepam• Lamotrigine• Lorazepam

Platelet inhibitors:• Clopidogrel

Musculoskeletal/analgesia:• NSAIDS

Lipid‐lowering:• Fibrates

Anti‐hyperglycemic:• Sulfonylureas

Opioids:• Morphine


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Products in Iowa

www.medpharmiowa.com/productswww.google.com/images

20:1(CBD:THC)

2:1(CBD:THC)

1:1(CBD:THC)

1:20(CBD:THC)

Capsule 20 mg:1 mg

5 mg:5 mg 0.25 mg:5 mg

0.5 mg:10 mg10 mg:10 mg

1 mg:20 mg

Tincture5 mg:0.25 mg/0.25 mL

~5 mg:5 mg/0.25 mL 0.25 mg:5 mg/0.25 mL25 mg:2 mg/0.25 mL

Cream17.5 mg:8.75 mg/0.5 tsp*

17.5 mg:8.75 mg/0.5 tspΩ

pediatric formulation; * = no scent; Ω = rosemary extract scent

What’s In Recreational?

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

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

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


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20:1(CBD:THC)

2:1(CBD:THC)

1:1(CBD:THC)

1:20(CBD:THC)

Capsule 20 mg:1 mg

5 mg:5 mg 0.25 mg:5 mg

0.5 mg:10 mg10 mg:10 mg

1 mg:20 mg

Tincture5 mg:0.25 mg/0.25 mL

~5 mg:5 mg/0.25 mL 0.25 mg:5 mg/0.25 mL25 mg:2 mg/0.25 mL

Cream17.5 mg:8.75 mg/0.5 tsp

17.5 mg:8.75 mg/0.5 tsp

20:1(CBD:THC)

2:1(CBD:THC)

1:1(CBD:THC)

1:20(CBD:THC)

Capsule $69.99/30 caps

$49.99/30 caps $33.99/30 caps

$64.99/30 caps$94.99/30 caps

$119.99/30 caps

Tincture$27.99/14 mL

$89.99/14 mL $79.99/14 mL$129.99/14 mL

Cream$79.99/56 g

$79.99/56 g

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


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Prescribing Review

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

#60 0 refills


“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.


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

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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

Sioux City

Council Bluffs

Windsor Heights

Davenport

Waterloo

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

Iowa Cannabis Statistics(3/25/19)


Role in Registry# of People (11/16/18)

# of People (11/30/18)

# of People (1/11/19)

# of People (2/1/19)

# of People (3/25/19)

Issued Cards: # patients with active, DOT‐issued cards

499 663 1197 1361 2170

Healthcare Practitioners:unique # of physicians who have certified patients

325 353 463 505 619

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Iowa Cannabis Statistics

“pain”= 61%

11/30/19

“pain”= 65%

2/1/19

“pain”= 67%

3/25/19

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=HSB244www.google.com/schoolhouserock

Iowa Legislation

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

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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


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

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Questions? Questions?

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Schleich, Kevin - Cannabinoids- Pharmacology, Medical ... · • Marijuana contains numerous extractable substances –Steroidal components –Volatile compounds • 60 cannabinoids