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MAKING CENTS OF

CANNABIS

Rocsanna Namdar Pharm.D., BCPS, FCCP

Disclosure

I have no financial disclosures or conflicts

of interest with the presented material in

this presentation.

Learning Objectives - Pharmacists

1. Describe the pharmacology of medical cannabis

pertaining to their potential medical applications

2. Identify and compare pharmacokinetic profiles of the

various formulations of medical cannabis

3. Review state laws and legal issues as they relate to

medical cannabis

4. Review the current data for medical uses of cannabis

5. Recognize the potential adverse effects of medical

cannabis

6. Discuss current trends surrounding medical cannabis

use and the role of the pharmacist

Learning Objectives - Technicians

1. Identify the general mechanism the pharmacology of

medical cannabis pertaining to their potential medical

applications

2. Review state laws and legal issues as they relate to

medical cannabis

3. Review the current data for medical uses of cannabis

4. Recognize the potential adverse effects of medical

cannabis

5. Discuss current trends surrounding medical cannabis

use

History of Federal Law

• 1911 – Prohibition begins

• 1937 – The Marijuana Tax Act – Prohibits cannabis at the federal level. Medical use is still permitted

• 1970 – Controlled Substances Act Classifies MJ as Drug with ”No Accepted Medicinal Use” • 1976 – Robert Randall petitioned for his medicinal use as “necessity”

• 1990: The Solomon–Lautenberg amendment is enacted. As a result, many states pass laws imposing mandatory driver's license suspensions for persons caught possessing cannabis, even if unrelated to driving.

• 2014: The Rohrabacher–Farr amendment passed the U.S. House and was signed into law. Requiring annual renewal, it prohibits the Justice Department from interfering with the implementation of state medical cannabis laws.

• 2018: The 2018 farm bill legalizes low-THC hemp nationwide and effectively deschedules hemp-derived cannabidiol (CBD) from the Controlled Substances Act

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The Controlled Substances Act -1970

• Five Schedules

• Marijuana is under

Schedule I

• “no currently

accepted medical

use…”

Federal Law: Medical Cannabis is Schedule I

Medical Cannabis is illegal

LawYEAR MILESTONE

1973 Decriminalization begins

1978 New Mexico passes law recognizing medical value. The controlled substances

therapeutic research act.

1996 Medical Cannabis begins: California voters pass Proposition 215 legalizing

medical marijuana

2007 New Mexico legislature passes SB 523, legalizing medical marijuana for

compassionate use

2009 Obama administration issues a memo to federal prosecutors encouraging them

to refrain from prosecuting people who distribute medical marijuana in

compliance with state laws

2012 Recreational Cannabis begins: Colorado and Washington state vote to legalize

recreational marijuana

2013 Obama administration issues the “Cole memo’ to federal prosecutors to limit

intervention in states that have legalized marijuana

2014 Rohrabacher-Farr amendment

2018 US Attorney General Jeff Sessions rescinds the Cole memo and other Obama

policies related to enforcement of federal marijuana laws in states that have

legalized marijuana – Confirmed by Attorney General William Barr

Law

Decriminalization

• Relaxation of criminal

penalties associated with

personal marijuana use

• 1973 – Oregon

decriminalized marijuana

Legalization

• Allows individual

marijuana possession

• Permits legal production

and sale of the drug

• Types of Legalization

• Medical Cannabis

• Recreational Marijuana

America’s Marijuana Revolution 2018

Variation of State and Federal Laws

• While various states have allowed the use of cannabis for

medical purposes, federal regulation still classifies as a

Schedule I Controlled Substance – indicating the federal

government does NOT recognize medical use of

cannabis.

• Pharmacists must comply with the law that is more

stringent – in this case, recognizing cannabis as a

Schedule I Controlled Substance

• Violation of federal statutes can result in fines,

imprisonment and/or the revocation of the pharmacy’s

DEA registration and immediately halting the dispensing

of controlled substances.

State Cannabis Programs – March 2019

MAP DOES NOT

REFLECT ILLINOIS

ACTION IN JUNE

2019 OR GUAM

ACTION IN APRIL

2019

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New Mexico Law

• April 2007

• NM became the 12th state to allow medical cannabis with the Lynn

and Erin Compassionate Use Act in 2007 (Senate Bill 523)

• The purpose of the Act is to allow the beneficial use of medical

cannabis in a regulated system for debilitating medical conditions

• March 2019

• House voted to pass recreational legalization; but was stalled

• April 2019

• Gov. Michelle Lujan Grisham signed Senate Bill 323 which

decriminalizes up to half ounce of marijuana.

• Starting July 1, 2019 – the penalty for possessing up to half an

ounce of marijuana will be $50 civil fine instead of potential civil

time.

New Mexico Law

What is a Cannabinoid?

• A drug that acts on the endocannabinoid system.

• The cannabis plant synthesizes many cannabinoids.

• 144 naturally occurring compounds known as

cannabinoids

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Some Components of

Cannabis

• Δ9 Tetrahydrocannabinol (THC)

• Cannabidiol (CBD)

• Cannabichromene

• Cannabigerol

• Tetrahydrocannabivarin

• Tetrahydrocannabinolic acid

• Cannabinol

• Terpenes

• Many others…….

Types of Cannabis

Sativa

• Provides more energetic

uplifting feeling

Indica

• Provides deep relaxation

Hybrid

Types of Products

• Cannabis based products for medicinal use

• Epidiolex

• Nabiximol (Sativex ®) NOT in USA

• Synthetic cannabinoids for medicinal use

• Dronabinol (Marinol®)

• Nabilone (Cesamet®)

• Non-Medicinal cannabidiol products

• Not scheduled or regulated as medicines

• Non-Medicinal cannabis

• Recreational use

• Non-Medicinal synthetic cannabinoids

• Spice

Very Basic Pharmacology

CB1 ReceptorsBrain

GI

Lungs

CB2 ReceptorsImmune System

Endogenous Cannabinoids

Pharmacokinetics - Metabolism: 11-OH THC (active) then THC-COOH (inactive)

Grotenhermen F. J of Cannabis Therapeutics. 2003

Didier ML. Cannabinoids in Nature and Med 2009

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Substance Enzyme Effect

THC Substrate: CYP3A4

CYP2C9

Inducer: CYP1A2

CBD Substrate: CYP3A4

CYP2C19

Inhibitor: CYP3A4

CYP2D6

Pharmacokinetics –

varied by administration route

Inhaled – Smoked• Onset within minutes

• Shorter duration

Biehl JR. Chest 2015

Pharmacokinetics –

varied by administration route

Oral – chocolate/brownies, sodas, gummies• Onset within hours

• Longer duration

-2 0

0 .1

1

1 0

1 0 0

1 0 0 0

0 .1 0 .3 0 .5 2 4 1 0 3 0 5 0

S m o k in g

V a p o r iz a t io n

O ra l

H o u rs

g

/L

Mean Blood THC Concentrations

in Occasional Smokers After 50.6 mg THC by

3 Administration Routes

LOQ=0.5

PharmacokineticsMean Blood 11-OH-THC in Occasional Smokers

After 50.6 mg THC by 3 Administration Routes

-2 0

0 .1

1

1 0

1 0 0

0 .1 0 .3 0 .5 2 4 1 0 3 0 5 0

S m o k in g

V a p o r iz a t io n

O ra l

H o u rs

g

/Lµ

LOQ=0.5 µg/L

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Pharmacokinetics –

varied by administration route

Svec CE. Pharm Purchasing and Prod 2016

Tolerance in Subjective “High”

Blood THC After Smoking 6.8% THC Cigarette

LOQ 1 µg/L

Desrosiers. Clin Chem 2014

TH

C >

5 μ

g/L

Pharmacokinetics –

varied by administration route

Topical – Balms

Absorption varies

Summit Daily News CO 2019

Cannabis PotencyChanges in Cannabis Potency over the

Last Two Decades (1995-2014)

ElSohly MA. Biol Psychiatry. 2016

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Changes in Cannabis Potency over the Last

Two Decades THC:CBD (1995-2014)

ElSohly MA. Biol Psychiatry. 2016.

<<

The Health Effects of Cannabis and

Cannabinoids

Committee on the Health Effects of Marijuana:

An Evidence Review and Research Agenda

National Academies of Sciences Engineering Medicine

2017

Therapeutic Effects - Evidence

• Conclusive or Substantial Evidence

• For the treatment of chronic pain in adults

• As antiemetic in the treatment of chemotherapy-induced nausea

and vomiting

• Improving patient-reported multiple sclerosis spasticity symptoms

• Moderate Evidence

• Improving short-term sleep outcomes in individuals with sleep

disturbance associated with obstructive sleep apnea syndrome,

fibromyalgia, chronic pain, and multiple sclerosis

National Academies of Sciences, Engineering, and Medicine. 2017

Review- Chronic Pain

Indication # Studies

(# pts)

Cannabinoid

(# studies)

Comparator Outcome Summary

Estimate

Favors Grade

Rating

Chronic

Pain

(neuropathic

& cancer

pain)

8 (1370) Smoked THC (1)

Nabiximols (7)

Placebo Pain reduction ≥30%

scores

FU 2-15 weeks

OR (95% CI),

1.41 (0.99 to

2.00)

CBM Mod

6 (948) Nabiximols Placebo Pain

Follow-up 2-14 weeks

WMD (95% CI),

−0.46 (−0.80 to

−0.11)

CBM Mod

3 (613) Nabiximols Placebo Pain

Follow-up 3-15 weeks

WMD (95% CI),

−0.17 (−0.50 to

0.16)

CBM Mod

6 (267) Nabiximols (5)

Nabilone (1)

Placebo Patient global

impression of change

Follow-up 3-14 weeks

OR (95% CI),

2.08 (1.21 to

3.59)

CBM Low

5 (764) Nabiximols (5) Placebo Neuropathic pain

Follow-up 5-15 weeks

WMD (95% CI),

−3.89 (−7.32 to

−0.47)

CBM Mod

3 (573) Nabiximols Placebo Quality of life

Follow-up 12-15 weeks

WMD (95% CI),

−0.01 (−0.05 to

0.02)

PBO Mod

Review - Chronic pain

Stockings E. Pain. 2018

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Review - Chronic pain

Whiting et al JAMA June 2015

Review –

Nausea & Vomiting due to Chemotherapy

Indication # Studies

(# pts)

Cannabinoid

(# studies)

Comparator Outcome Summary

Estimate

Favors Grade

Rating

Nausea &

Vomiting due

to

Chemotherapy

3(102) Dronabinol (2)

Nabiximol (1)

Placebo Nausea &

Vomiting

Complete

Response

OR (95% CI),

3.82 (1.55 to

9.42)

CBM Low

NCCN & ASCO: Cannabinoids such as dronabinol can be considered for

refractory nausea and vomiting

28 studies: 14 Nabilone

3 Dronabinol1 Nabiximol

4 Levonantradol

6 THC

Whiting et al JAMA June 2015

Indication # Studies

(# pts)

Cannabinoid

(# studies)

Comparator Outcome Summary Estimate Favors Grade

Rating

Spasticity

due to MS

or

paraplegia

2 (519) Nabiximols Placebo 50% ↓ in

spasticity symptoms

FU 6-14 wks

OR (95% CI), 1.40

(0.81 to 2.41)

CBM Low

2 (519) Nabiximols Placebo 30% ↓ in

spasticity symptoms

FU 6-14 wks

OR (95% CI), 1.64

(0.95 to 2.83)

CBM Low

5 (1244) Nabiximols

(4)

THC/CBD (1)

Placebo Spasticity

FU 3-15 wks

WMD (95% CI),

−0.11 (−0.23 to 0.02)−0.32 (−1.59 to 0.95)

−0.94 (−2.37 to 0.49)

CBM Mod

3 (698) Nabiximols

(2)

Nabilone (1)

Placebo Spasticity WMD (95% CI),

−0.76 (−1.38 to −0.14)

CBM Low

4 (1433) Nabilone (2)

THC/CBD (1)

Dronabinol

(1)

Placebo ADLs WMD (95% CI),

−0.58 (−1.73 to 0.56)0.23 (−0.13 to 0.59)

−0.03 (−0.39 to 0.33)

PBO Mod

2 (497) Nabiximols Placebo Walking

speed

WMD (95% CI),

−0.86 (−3.08 to 1.36)

PBO Mod

3 (461) Nabiximols Placebo Pt global impr

of change

OR (95% CI), 1.44

(1.07 to 1.94)

Low

Whiting et al JAMA June 2015

Review – Sleep Disorders

Indication # Studies

(# pts)

Cannabinoid

(# studies)

Comparator Outcome Summary

Estimate

Favors Grade

Rating

Sleep

Disorders

1(22) Nabilone Placebo Sleep

apnea/hypop

nea

Apnea Index

FU 3 wks

Mean

difference -

19.64

P=0.02

CBM Low

8 (539) Nabiximols (7)

THC/CBD(1)

Placebo Sleep Quality

FU 2-15 wks

WMD (95%

CI)

-0.58 (-0.87

to -0.29)

CBM Very

Low

3 (1637) Nabiximols Placebo Sleep

Disturbance

FU 2-15 wks

WMD (95%

CI)

-0.26 (-0.52

to 0.00)

CBM Very

Low

Whiting et al JAMA June 2015

Therapeutic Effects - Limited Evidence

• Increasing appetite and decreasing weight loss associated with HIV/AIDs

• Improving clinician-measured multiple sclerosis spasticity symptoms

• Tourette syndrome

• Anxiety symptoms, as assessed by a public speaking test,

• Posttraumatic stress disorder in individuals with social anxiety disorders

• Traumatic Brain Injury

• Glaucoma

• Dementia

• Depressive symptoms in chronic pain or multiple sclerosis

Review - PTSD

• No clinical trials

• Pilot study showed reduction in symptoms and improvement in sleep (THC 5 mg)

• Few observational studies

• Open label (N=47) – nabilone (synthetic cannabinoid) shown to improve nightmares. Subjective improvement in sleep time, the quality of sleep, and the reduction of daytime flashbacks and nightsweats

• Potential benefit for a variety of PTSD symptoms. However, all studies have major limitations as none have yet been randomized, controlled, clinical trials with active marijuana use

Shishko I mental health clinician 2018

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Therapeutic Effects - Insufficient Evidence

• Cancer, including glioma

• Cancer associated anorexia

• Epilepsy

• Spasticity in patients with paralysis due to spinal cord injury

• Irritable bowel syndrome

• Amytrophic Lateral Sclerosis

• Huntington’s Disease

• Parkinson’s Disease

• Dystonia

• Achieving abstinence in the use of addictive substances

• Mental health outcomes in schizophrenia

Review - Autism

• Research is limited to case reports, abstracts and studies

in children with disorders associated with autism spectrum

disorder. (intellectual disability, epilepsy)

• Open label trial 7/10 pts Dronabinol – associated with

improvements in self injurious behavior

• Trials underway

• Cannabidivarin (CBDV) vs. placebo in children with autism

spectrum disorder ASD

• Cannabinoids for behavioral problems in children With ASD

Medical Cannabis Laws and Opioid Analgesic Overdose

Mortality in the United States, 1999-2010

JAMA Intern Med. 2014;174(10):1668-1673. doi:10.1001/jamainternmed.2014.4005

Association Between Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in Each Year After Implementation of Laws

in the United States, 1999-2010Point estimate of the mean difference in the opioid analgesic overdose mortality rate in states with

medical cannabis laws compared with states without such laws; whiskers indicate 95% CIs.

Impact of Cannabis on Opioid Use

• When used in conjunction with opioids, cannabinoids can

lead to greater cumulative relief of pain and potential

reduction of opiate use

• Potentially less dangerous

• Hypothesis - If medical marijuana is available as an option

for dealing with pain, some people might use it instead of

opioids

• Studies don’t show causality

• More studies and larger clinical trials are needed to

confirm this finding

Other Health Effects - Substantial Evidence

• Worse respiratory symptoms (long term)

• Increased risk of motor vehicle crashes

• Lower birth weight of offspring

• Development of schizophrenia or other psychosis with the

highest risk among frequent users

• Risk Factors for Problem Use

• Being male and smoking cigarettes

• Initiating cannabis use at an earlier age

• Stimulant treatment of ADHD during adolescence is not a risk for

problem use

Other Health Effects - Moderate Evidence

• No association b/w lung, head & neck cancers

• Cessation of cannabis smoking and improvement in respiratory symptoms

• Increased risk of overdose injuries, including respiratory distress, among pediatric populations in US where cannabis is legal

• Impairment of cognitive domains of learning, memory, and attention

• Better cognitive performance among pts with psych disorders

• Increased symptoms of mania/hypomania in bipolar disorder

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Other Health Effects - Moderate Evidence

• Increased risk for the development of depressive disorders

• Increased incidence • suicidal ideation and suicide attempts

• suicide completion

• social anxiety disorder

• No worsening of negative symptoms in schizophrenia

• Anxiety, personality and bipolar disorders and adolescent ADHD are not risk factors for development of problem use

• Major depression is a risk factor for development of problem use

• During adolescence the freq of cannabis use, oppositional behaviors, younger age of first alcohol us, nicotine use, parenteral substance use, poor school performance, antisocial behaviors, and childhood sexual abuse are risk factors for problem use

Adverse Effects

Adverse Effect Odds Ratio

Disorientation 5.41 (2.61-11.19)

Dizziness 5.09 (4.10-6.32)

Euphoria 4.08 (2.18-7.64)

Confusion 4.03 (2.05-7.97)

Drowsiness 3.68 (2.24-6.01)

Dry Mouth 3.50 (2.58-4.75)

Nervous System Disorders 3.17 (2.20-4.58)

Psychiatric Disorders 3.10 (1.81-5.29)

Somnolence 2.83 (2.05-3.91)

Hallucination 2.19 (1.02-4.68)

Paranoia 2.05 (0.42-10.10)

Whiting et al JAMA June 2015

Wynn RL. Clin Drug Info 2015

Brain

Development

Accumbens

• Immediate Rewards

• Impulsive Behavior

Cortex

• Long Term Gain

• Thoughtful Behavior

Adolescents Differ in Substances Abused

SAMHSA, Center for Behavioral Health Statistics and Quality, National Survey on Drug Use and Health, 2013.

New Marijuana Initiates (Age 12+)

2017 National Survey on Drug Use and Health

Monthly Calls to Poison Center (mean)

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Copyright 2019 American Medical

Association. All Rights Reserved.

Association of Cannabis Use in Adolescence and Risk of Depression,

Anxiety, and Suicidality in Young Adulthood: A Systematic Review and

Meta-analysis

JAMA Psychiatry. 2019;76(4):426-434. doi:10.1001/jamapsychiatry.2018.4500

Forest Plot Showing Adjusted Odds Ratio (OR) and 95% CIs for Suicidal Ideations and Attempts According to Cannabis Use in

Individual Studies

Copyright 2019 American Medical

Association. All Rights Reserved.

Association of Cannabis Use in Adolescence and Risk of Depression, Anxiety,

and Suicidality in Young Adulthood: A Systematic Review and Meta-analysis

JAMA Psychiatry. 2019;76(4):426-434. doi:10.1001/jamapsychiatry.2018.4500

Forest Plot Showing Adjusted Odds Ratio (OR) and 95% CIs for Depression and Anxiety in Young Adulthood According to Cannabis

Use in Individual Studies

Adolescent vulnerability

Madeline H. Meier et al. PNAS 2012©2012 by National Academy of Sciences Schizophrenia Bulletin, Volume 40, Issue 6, November 2014, Pages 1509–1517, https://doi.org/10.1093/schbul/sbt181

.

Cannabis use is associated with an earlier

age of onset

National Academies Recommendations

• Address Research Gaps• To develop a comprehensive evidence base on the short- and long-

term health effects of cannabis use (both beneficial and harmful effects)

• Improve Research Quality• To promote the development of conclusive evidence on the short- and

long-term health effects of canna bis use (both beneficial and harmful effects)

• Improve Surveillance Capacity• To ensure that sufficient data are available to inform research on the

short- and long-term health effects of cannabis use (both beneficial and harmful effects)

• Address Research Barriers• A committee of experts tasked to produce an objective and evidence-

based report that fully characterizes the impacts of regulatory barriers to cannabis research and that proposes strategies for supporting development of the resources and infrastructure necessary to conduct a comprehensive cannabis research agenda

National Academies of Sciences, Engineering, and Medicine. 2017

Pharmacist’s Clinical Concerns

• Limited Efficacy and Safety Data

• Lack of scientific data on cannabis and lack of guidance

by the FDA leaves pharmacists ill prepared to make

clinically sound decisions when assessing cannabis

therapy and inhibits pharmacists ability to educate

patients

• Legal liability stemming from federal regulation

• Pharmacists are hesitant to jeopardize their career by

being involved

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Role of Pharmacists

• As with any substance for medical use, pharmacists are expected to complete a prospective drug utilization for review to assess: • Appropriateness of therapy

• Appropriate drug, dose, route, duration

• Drug interactions

• Contraindications

• Abuse and misuse

• Pharmacists are expected to provide education and counseling

• Pharmacists must be aware of how cannabis use affects patients

Conclusion

• Large gap between the public perception of cannabis and

the medical establishment view as data is lacking

• Mainstream has accepted medical cannabis to be

effective in many conditions; but clinical studies are few

• Only few studies are prospective and most are not

placebo controlled, not blinded and have small sample

sizes.

Conclusion

• Cannabis use also has adverse effects that raise patient

safety issues

• Lack of credible data causes serious challenges for

pharmacists to perform their responsibilities as a

pharmacist and advocate for appropriate patient care

• Consistency in quality and purity remain a concern

• Federal law still states that marijuana is Schedule I

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