Download Going Green: What the Legalization of Marijuana Means for

Going Green: What the
Legalization of Marijuana
Means for Pharmacists
Laura M. Borgelt, PharmD, FCCP, BCPS, NCMP
Skaggs School of Pharmacy and Pharmaceutical Sciences
University of Colorado Anschutz Medical Campus
William J. Stilling, B.S. Pharm., M.S., J.D.
Parsons Behle & Latimer
Salt Lake City, Utah
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Supporter
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Disclosures
• Dr. Borgelt has served as a member of six working groups in Colorado:
• Colorado Department of Public Health and Environment (CDPHE):
• Cosponsored by the American Society for Pharmacy Law.
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Amendment 64 (Marijuana Legalization) Task Force Working Group:
Consumer Safety and Social Issues
State Licensing Authority Labeling, Packaging, Product Safety and Marketing
State Licensing Authority Medical and Retail Marijuana Mandatory Testing
and Random Sampling
State Licensing Authority Serving Size and Product Potency
CDPHE Retail Marijuana Public Health Advisory Committee
CDPHE Pregnancy and Breastfeeding Guidelines Committee
The American Pharmacists Association is accredited by the Accreditation
Council for Pharmacy Education as a provider of continuing pharmacy
education.
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Abbreviations
• Target Audience: Pharmacists and Pharmacy Technicians
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• ACPE#: 0202-9999-16-027-L03-P
0202-9999-16-027-L03-T
• Activity Type: Knowledge-based
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© 2016 by the American Pharmacists Association. All rights reserved.
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ATF
CBD
CSA
DOJ
MMJ
SCOTUS
(Bureau of) Alcohol, Tobacco, and Firearms
Cannabadiol
Controlled Substances Act
Department of Justice
Medical MariJuana
The United States Supreme Court
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Learning Objectives
Outline
• At the completion of this knowledge-based activity,
participants will be able to:
• Introduction to marijuana and rationale for potential
1. Describe the legal issues that arise when patients of a hospital or
retail pharmacy are using marijuana lawfully under state laws.
2. Describe the laws and regulations governing clinical research that
uses marijuana.
3. Discuss the impact state and federal marijuana laws have on
pharmacists who intend to be involved in marijuana business that is
lawful under state laws.
4. Summarize the holdings of recent court decisions interpreting state
marijuana laws.
5. Describe the conflicts between state and federal marijuana laws.
6. Explain how to find reliable sources to know the laws governing
marijuana in states where the attendee practices pharmacy.
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medical uses
Pharmacology
Federal laws
State laws
Pharmacokinetics Smoked vs. Eaten
Therapeutic Effectiveness of MMJ
• Discussion of clinical and research conflicts
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1. Which of the following forms of marijuana has the
Intravenous
Inhaled
Oral
Buccal
A.
B.
C.
D.
E.
F.
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4. Which of the following is NOT true
about federal cannabis law?
addressing the DOJ’s (and DEA’s) ability to enforce
federal controlled substances laws?
A. The court ruled the DEA cannot impose penalties or shut
A. Marinol (Dronabinol) capsules are available for commercial
down dispensaries acting lawfully under state law.
B. The court ruled the Supremacy Clause of the U.S.
Constitution allows the DEA to arrest marijuana dispensers
because marijuana is a schedule I substance.
C. The court ruled pharmacists were permitted to be involved in
marijuana dispensaries because they were acting lawfully
under state law.
D. The court ruled owners of dispensaries could be arrested
because of the quantity of marijuana they possessed, but
patients could not be arrested.
© 2016 by the American Pharmacists Association. All rights reserved.
Cancer
Epilepsy
Glaucoma
Muscle spasms
Nausea
Pain
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3. Which is true about a recent federal court case
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2. Which of the following is the most common
reason for MMJ use in Colorado?
slowest onset of action?
A.
B.
C.
D.
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use.
B. Smoked cannabis is a C-I controlled substance.
C. Pharmacies may not dispense C-I controlled substances.
D. The DEA may not enforce its laws to prevent states from
implementing their own state laws
E. A series of memoranda from the DOJ prohibit the DEA from
enforcing federal marijuana laws in states where marijuana is
legal for medical use.
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6. Poll Question
5. Which of the following is true?
I know someone who consumes marijuana
for medical or recreational purposes.
A. Pharmacists should never ask patients if they are using
marijuana or taking illicit drugs
B. Pharmacists should never put information about patient’s
marijuana use in the patient profile
C. Pharmacists should counsel patients never to use marijuana
D. Pharmacists should counsel patients about known drug-drug
interactions with marijuana
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A. Yes, medical purposes only
B. No, recreational purposes only
C. Yes, both
D. No
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7. Poll Question
I believe the most common reason
people seek out marijuana is to...
INTRODUCTION TO MARIJUANA
AND RATIONALE FOR
POTENTIAL MEDICAL USES
A. Relieve pain
B. Improve symptoms of nausea and vomiting
C. Relieve muscle spasms associated with multiple sclerosis
D. Get high
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A Few Questions to Consider
Patient Case in Colorado
• 47 y.o. male with PMH of hypertension, diabetes,
• Are there other ways for him to consume MMJ to avoid the
risks of smoking?
peripheral neuropathy, and chronic pain
• Is MMJ effective for the treatment of pain?
• What adverse effects might this patient experience with
– Pain Treatment Regimen
• Oxycontin 30mg po BID and oxycodone 5 mg po prn
• His pain medications have not changed in over one year
• Today, he admits that he has also been smoking medical
marijuana twice daily for the past two years to help his pain
(decreased from 8/10 to 4/10)
• He has been afraid to tell the healthcare team about this
because he believes they will not “approve” of this treatment.
He states he saw a different physician to get his card and
recommendation for MMJ
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© 2016 by the American Pharmacists Association. All rights reserved.
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chronic use of inhaled MMJ?
Are there any drug interactions with MMJ?
How might MMJ impact his opioid use?
What other issues might this patient need to consider?
How can I create an environment where patients feel safe to
talk with me about all treatments they use?
• What federal and state laws impact my ability to appropriately
care for this patient?
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Marijuana
Key Opinion
• FDA approved products
– Single molecule pharmaceuticals
• Dronabinol (Schedule III)
• Nabilone (Schedule II)
– Liquid extract: nabiximols (Sativex®)
• Approved in 27 countries; U.S. - Phase III trials
– Liquid extract: cannabidiol (Epidiolex®)
• FDA: orphan drug status for Dravet and Lennox-Gastaut
syndromes
• Expanded access INDs to several independent investigators
Considerations for medical use of marijuana
are different than considerations for
recreational use of marijuana.
Medical use: benefit - risk
• Phytocannabinoid-dense botanicals
• Cannabis sativa – medicinal plant (Schedule I)
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Recreational use: risk - risk
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Cannabis
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Plant-derived cannabinoids
∆9 -tetrahydrocannabinol - THC
∆8 -tetrahydrocannabinol - THC
Cannabidiol – CBD
Cannabinol - CBN
Cannabigerol - CBG
Cannabichromene - CBC
Cannabicyclol - CBL
Cannabielsoin - CBE
Cannbitriol - CBT
Miscellaneous
Cannabinodiol (air-oxidation)
Br J Pharmacology 2006;147:S163-71
Br J Pharmacology 2011;163:1344-64
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Endogenous Cannabinoid System
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Endogenous Cannabinoid System
• Endocannabinoids and their receptors found throughout body:
 Endocannabinoids and their receptors found throughout body:

– Brain, organs, connective tissues, glands, and immune cells.
Brain, organs, connective tissues, glands, and immune cells.
 In each tissue, the cannabinoid system performs different tasks; goal is
always homeostasis
 When cannabinoid receptors are stimulated, a variety of physiologic
processes occur
 CB1 receptors: nervous system, connective tissues, organs, glands
 CB2 receptors: immune system and associated structures
 Endocannabinoids are substances our bodies make naturally to
stimulate CB1 and CB2
 Anandamide
 2-arachidonoylglycerol (2-AG)
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© 2016 by the American Pharmacists Association. All rights reserved.
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• In each tissue, the cannabinoid system performs different tasks; goal is
always homeostasis
• When cannabinoid receptors are stimulated, a variety of physiologic
processes occur
– CB1 receptors: nervous system, connective tissues, organs, glands
– CB2 receptors: immune system and associated structures
• Endocannabinoids are substances our bodies make naturally to
stimulate CB1 and CB2
– Anandamide
– 2-arachidonoylglycerol (2-AG)
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Endogenous Cannabinoid System
Endogenous Cannabinoid System
• Endocannabinoids and their receptors found throughout
• When cannabinoid receptors are stimulated, a variety of
body:
–
–
–
–
–
physiologic processes occur
Brain
Organs
Connective tissues
Glands
Immune cells
– CB1 receptors: nervous system, connective tissues, organs,
glands
– CB2 receptors: immune system and associated structures
• Endocannabinoids are substances our bodies make
naturally to stimulate CB1 and CB2
• In each tissue, the cannabinoid system performs different
– Anandamide
– 2-arachidonoylglycerol (2-AG)
tasks
– Goal is always homeostasis
http://norml.org/library/item/introduction-to-the-endocannabinoid-system Accessed February 5, 2016
Neuro Endocrinol Lett. 2008 Apr;29(2):192-200.
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Endogenous Cannabinoid System
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Endogenous Cannabinoid System
• Endocannabinoids and their receptors found throughout
What happens when there is potential
endocannabinoid deficiency,
dysregulation, destabilization, or
decreased binding?
•
body: brain, organs, connective tissues, glands, and
immune cells.
In each tissue, the cannabinoid system performs different
tasks; goal is always homeostasis
What happens when there is potential
endocannabinoid deficiency,
dysregulation, destabilization, or
decreased binding?
http://norml.org/library/item/introduction-to-the-endocannabinoid-system Accessed Febr
Neuro Endocrinol Lett. 2008 Apr;29(2):192-200.
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Endogenous Cannabinoid System
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Endocannabinoid System
• When cannabinoid receptors are stimulated, a variety of
physiologic processes occur
– CB1 receptors:
• Nervous system
• Connective tissues
• Gonads
• Glands
• Organs
– CB2 receptors:
• Immune system and associated structures
• Endocannabinoids are substances our bodies make
naturally to stimulate CB1 and CB2
– Anandamide
– 2-arachidonoylglycerol (2-AG)
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© 2016 by the American Pharmacists Association. All rights reserved.
Reprinted with permission. Nat Rev Gastroenterol Hepatol. 2014;11(3):142-3
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Targets of Marijuana
Cannabis Pharmacology
CB2 Receptors
CB1 Receptors
• Basal ganglia
• Motor activity
• Cerebellum
• Motor coordination
• Hippocampus
• Short-term memory
• Neocortex
• Thinking
• Hypothalamus & limbic
• Appetite, sedation
• Pertaqueductal gray dorsal
horn
• Pain
• Immune cells
http://www.tokeofthetown.com/2011/03/worth_repeating_bodys_own_cannabinoids_are_the_bli.php
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• Immunologic cells
• B lymphocytes
• Natural killer cells
• Brain
• Role not established
Brit J Clin Pharm 2009;67(1):5-21
J Psychopharmacol 2008;22:707–16
J Psychopharmacol 2008;22:717–26.
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Endocannabinoid System
TH
C
Reprinted with permission. Nat Rev Gastroenterol Hepatol. 2014;11(3):142-3
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
Other G-protein receptors: GPR55, GPR55940, etc.

G-protein-coupled receptors: noncompetitive inhibitor at
and -opioid receptors, NE, DA, 5-HT

Ligand-gated ion channels: allosteric antagonism at 5-HT3,
nicotinic, and enhance activation of glycine receptors

Transient receptor potential channels (TRPVs): bind and
activate TRPV1 similar to capsaicin, also CB1 receptors are
located near TRPV1

Ion channels: inhibition of Ca, K, Na channels by noncompetitive antagonism

Peroxisome Proliferator-Activated Receptors: PPAR and
PPAR are activated
© 2016 by the American Pharmacists Association. All rights reserved.
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Another Kid on the Block…
Non-Cannabinoid Targets Linked to Cannabis
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Other cannabinoids found in the plant are also providing effects.
The cannabinoid that has sparked the most interest is a nonpsychoactive component called cannabidiol (CBD).
μ-
Little binding affinity to CB1 / CB2
Suppresses enzyme fatty acid amide
hydroxylase (“FAAH”) – the enzyme
that breaks down anandamide
Opposes THC
at CB1 receptor
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Stimulates
release of 2-AG
Epilepsia 2014;55(6):791–802.
http://www.projectcbd.org/news/how-cbd-works/
Accessed 12/23/15
TRPV-1
receptor
agonist
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5-HT1A
receptor
activation
GPR55
antagonist
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Potential Physiologic Responses to Cannabis
Improves sleep
Anti-seizure effects and neuroprotection
- Coughing
- Wheezing
- Sputum
production
- Tachycardia
- Palpitations
- Hypertension
Reduces anxiety and psychotic symptoms/PTSD
Marijuana
Adverse
Effects
Prevents nausea and stimulates appetite
Reduces intraocular pressure
Bronchodilator
Nervous System
Relaxes muscles and reduces muscle spasms
Relieves pain (especially neuropathic)
Anti-inflammatory
Anti-proliferative
Anti-viral
- Lethargy, Sedation, Slowed Reaction Time
- Psychological dysfunction
- impaired coordination, memory formation, recollection, focus)
- Visual Disturbances
With potential adverse
effects.
Minnesota Medicine 2014:4:18-27.
http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq.
Accessed February 5, 2016.
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Am J Health-Syst Pharm. 2007; 64:1037-1044. Pharmacotherapy 2013;33:195-209.
http://www.drugabuse.gov/publications/drugfacts/marijuana Drug Facts: Marijuana
Accessed February 5, 2016.
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Adverse Effects of Marijuana
Effects of Short-term Use
 Impaired short-term
memory
 Impaired motor
coordination
 Altered judgment
 Motor vehicle accidents
(2x)
 Paranoia and psychosis
(high doses)
Drug Interactions
Effects of Long-term/Heavy Use
 Addiction (9% overall)
 Altered brain development*
 Cognitive impairment (with lower
IQ)*
 Diminished life satisfaction and
achievement*
 Poor educational outcome
 Symptoms of chronic bronchitis
 Increased risk of chronic psychosis
disorders
*Effect is strongly associated with initial marijuana use early in adolescence
N Engl J Med 2014;370:2219‐27.
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Cannabinoid
CYP-450
2C9
Δ9-THC
CYP-450
2C19
CYP-450
3A4
*
*
Δ8-THC
*
*
CBD
*
CBN
*
*
*
Drug Metab Rev. 2014;46(1):86–95
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Application of Information
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Application of Information
• 2C9, 2C19, and 3A4 INHIBITORS may increase the
• THC is a CYP1A2 Inducer
pharmacological effect and duration of THC
– Macrolides (except azithromycin), oral contraceptives, cannabidiol
(CBD), paroxetine, fluoxetine, and some PPI’s, HIV antiretrovirals,
calcium channel blockers, and antifungals
– May decrease pharmacological effect of theophylline, clozapine,
chlorpromazine.
• NOTE: CBD is powerful inhibitor of CYP3A4 and CYP2D6
– May increase the bioavailability and pharmacological effect of
macrolide antibiotics, calcium channel blockers, antihistamines,
haloperidol, sildenafil
• 2C9, 2C19, and 3A4 INDUCERS may decrease the
pharmacological effect and duration of THC
• NOTE: Carbamazepine, rifampin, phenytoin, ritonavir, St.
John’s Wort, phenobarbital
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© 2016 by the American Pharmacists Association. All rights reserved.
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Impact of MMJ on Opioid Use
Key Point
• When used in conjunction with opioids, cannabinoids
•
can lead to greater cumulative relief of pain and
potential reduction of opiate use
Comparisons in analgesia
Marijuana consists of 60+ cannabinoids.
The effects of marijuana are dependent on
many factors and very complex. Benefits
and risks should be weighed carefully for
individual patients.
– 10 mg THC less effective than 60 mg codeine
– 20 mg THC more effective than 120 mg codeine
• Prevent development of tolerance to and withdrawal
•
from opiates and potentially rekindle opiate analgesia
after a prior dosage has become ineffective
Potentially less dangerous than opiates (no direct
death)
J Psychoactive Drugs 2012;44:125-33
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Treaty—Single Convention on Narcotic
Drugs 1961
• Signed by U.S. and 183 other countries
• Cannabis deemed a banned substance
• Article 28 provides:
Federal Laws
1. If a Party permits the cultivation of the cannabis plant for the
production of cannabis or cannabis resin, it shall apply thereto the
system of controls as provided in article 23 respecting the control of
the opium poppy.
2. This Convention shall not apply to the cultivation of the cannabis
plant exclusively for industrial purposes (fibre and seed) or
horticultural purposes.
3. The Parties shall adopt such measures as may be necessary to
prevent the misuse of, and illicit traffic in, the leaves of the
cannabis plant.
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Treaty—Single Convention on Narcotic
Drugs 1961
See, Fink, J.L., Marijuana Producers and Distributors:
The Evolving Federal Enforcement Philosophy,
Rx Ipsa Loquitur, 42:2; March/April 2015.
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Federal Law—Controlled Substances Act
• Cannabis is defined as:
“[M]arihuana" means all parts of the plant Cannabis sativa L., whether
growing or not; the seeds thereof; the resin extracted from any part of
such plant; and every compound, manufacture, salt, derivative,
mixture, or preparation of such plant, its seeds or resin.
21 USC§802(16).
[T]he flowering or fruiting tops of the cannabis
plant (excluding the seeds and leaves when not
accompanied by the tops) from which the resin
has not been extracted, by whatever name they
may be designated.
• Schedule I includes:
– Tetrahydrocannabinol, and five other related substances including
isomers and stereochemical variants.
• Legal implications: Treaties take precedence over federal
and state laws.
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© 2016 by the American Pharmacists Association. All rights reserved.
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Federal Law--Penalties
Possession
Fine
Prison
First
$1,000
Up to 1 year
Second
$2,500
Mandatory
minimum 15
days
$5,000
• Gonzales v. Raich, 545 U.S. 1 (2005)
Sale
Offense
Additional
The Supreme Court Speaks
Mandatory
minimum 90
days (up to 3
years)
Amount
< 50 kg
Fine *
(Individual)
$250,000
Fine
(Entity)
$1,000,000
Prison
5 years
50 - 99 kg
$1,000,000
$5,000,000
20
100 - 999 kg
$5,000,000
$25,000,000
5 to 40
≥ 1000 kg
$10,000,000 $50,000,000
10 - life
* Penalties are maximums
21 USC§841
Gifting “small amount” is same as possession
– Marijuana users and growers in California sought declaratory relief
declaring the Federal Controlled Substances Act unconstitutional
as applied to their activities permitted by the California
Compassionate Use Act.
– SCOTUS ruled that Congress’s power under the Commerce
Clause includes the power to prohibit local cultivation and use of
marijuana because such local activity can substantially affect
interstate commerce.
21 USC § 844
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Federal Law—Evolving Views
Law by Memoranda (2009—Ogden)
Federal Law—Evolving Views
Law by Memoranda (2009—Ogden)
• Ogden 2009 Memo—Conduct that may indicate illegal activity of
• “Ogden Memo” October 19, 2009
potential federal interest:
– Investigations and Prosecutions in States Authorizing the Medical
Use of Marijuana
• David W. Ogden, Deputy Attorney General
• Guide to the exercise of investigative and prosecutorial
discretion
• Generally will not pursue “individuals whose actions are in
clear and unambiguous compliance with existing state
laws providing for the medical use of marijuana.”
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Federal Law—Evolving Views
Law by Memoranda (2011—Cole)
– Guidance Regarding the Ogden Memo in Jurisdictions Seeking to
Authorize Marijuana for Medical Use
• James M. Cole, Deputy Attorney General
• Response to state and local government inquiries
• Reiterated Ogden Memo guidance
• Recognized increased scope of commercial sale, cultivation,
distribution and use of marijuana for “purported medical purposes.”
• Ogden Memo was not a shield from federal prosecution of such
activities.
• Persons in such businesses and those who “knowingly facilitate
such activities are in violation of the Controlled Substances Act.”
• Those engaged in transactions involving proceeds from such
activities may be in violation of federal money laundering laws.
© 2016 by the American Pharmacists Association. All rights reserved.
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Unlawful possession or unlawful use of firearms;
Violence;
Sales to minors;
Financial and marketing activities inconsistent with the terms, conditions, or
purposes of state law, including evidence of money laundering activity and/or
financial gains or excessive amounts of cash inconsistent with purported
compliance with state or local law;
– Amounts of marijuana inconsistent with purported compliance with state or local
law;
– Illegal possession or sale of other controlled substances; or
– Ties to other criminal enterprises.
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Federal Law—Evolving Views
Law by Memoranda (2013—Cole)
• “2011 Cole Memorandum”—June 29, 2011
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• “2013 Cole Memorandum”—August 29, 2013
– Guidance Regarding Marijuana Enforcement
• James M. Cole
• Updated Ogden Memo in light of state ballot initiatives that
legalize possession of small amounts of marijuana
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Federal Law—Evolving Views
Law by Memoranda (2013—Cole)
Federal Law—Evolving Views
Law by Memoranda (2013—Cole)
DOJ Marijuana Enforcement Priorities
• DOJ’s guidance rests on its expectation that states and local
governments will implement strong and effective regulatory and
enforcement systems that will address the threat those laws could
pose to public safety, public health, and other law enforcement
interests.
• A system adequate to that task must not only contain robust controls
and procedures on paper; it must also be effective in practice.
• States must provide the necessary resources and demonstrate the
willingness to enforce their laws and regulations in a manner that
ensures they do not undermine federal enforcement priorities.
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GAO Report—December 2015
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Restricting Federal Enforcement
• STATE MARIJUANA LEGALIZATION: DOJ Should Document Its
Approach to Monitoring the Effects of Legalization
– “GAO was asked to review issues related to Colorado’s and
Washington’s actions to regulate recreational marijuana and DOJ’s
mechanisms to monitor the effects of state legalization.”
– “GAO recommends that DOJ document a plan specifying its
process for monitoring the effects of state marijuana legalization,
and share the plan with DOJ components.”
• In 2014, Congress passed the 2015 Appropriations Act.
• Section 538 reads:
None of the funds made available in this Act to the Department of
Justice may be used, with respect to the States of Alabama, Alaska,
Arizona, California, Colorado, Connecticut, Delaware, District of
Columbia, Florida, Hawaii, Illinois, Iowa, Kentucky, Maine, Maryland,
Massachusetts, Michigan, Minnesota, Mississippi, Missouri, Montana,
Nevada, New Hampshire, New Jersey, New Mexico, Oregon, Rhode
Island, South Carolina, Tennessee, Utah, Vermont, Washington, and
Wisconsin, to prevent such States from implementing their own
State laws that authorize the use, distribution, possession, or
cultivation of medical marijuana.
• Section 538 was included in the Appropriations Act of 2016.
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Medical Marijuana
DEA Authority to Enforce Controlled Substances Act
Medical Marijuana
DEA Authority to Enforce Controlled Substances Act
– REASONING: The court explained:
Marijuana (“MAMM”), and Lynette Shaw, No. C 98-00086
N.D. Cal. Oct. 19, 2015)
– RELIEF SOUGHT: Medical marijuana dispensary asked the court
to dissolve a permanent injunction that prohibited it from
dispensing medical marijuana under California’s Compassionate
Use Act because Congress prohibited the Department of Justice
(“DOJ”) from using any resources to interfere with a state’s ability
to implement its own medical marijuana laws.
– ISSUE: Does Congress’s ban on DOJ’s interference with
implementation of state medical marijuana laws warrant lifting the
permanent injunction against MAMM?
© 2016 by the American Pharmacists Association. All rights reserved.
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• U.S. v. MAMM
• United States of America v. Marin Alliance For Medical
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The plain reading of the text of Section 538 forbids the
[DOJ] from enforcing this injunction against MAMM to the
extent that MAMM operates in compliance with California
law.
The Government's contrary reading so tortures the
plain meaning of the statute that it must be quoted to
ensure credible articulation. (emphasis added)
Where to start?
An initial matter, perhaps, is the
contradiction inherent in the Government's assertion that
enjoining any one medical marijuana dispensary—here,
MAMM—does not impede California's implementation of its
medical marijuana laws.
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Medical Marijuana
Medical Marijuana
DEA Authority to Enforce Controlled Substances Act
DEA Authority to Enforce Controlled Substances Act
• U.S. v. MAMM
– The court explained that the government’s “drop-in-the-bucket is at
odds with fundamental notions of the rule of law.”
– Section 538 does not allow a little bit of enforcement.
– Congress chose to ban enforcement of federal laws by prohibiting
the use of funds for such efforts.
It defies language and logic for the Government to argue
that it does not "prevent" California from "implementing" its
medical marijuana laws by shutting down these same
heavily-regulated medical marijuana dispensaries; whether it
shuts down one, some, or all, the difference is of degree, not
of kind.
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Medical Marijuana
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Medical Marijuana
In April 2015, the drafters of §538 responded to the DOJ’s “recent
statements indicating that the [DOJ] does not believe a spending
restriction designed to protect [the medical marijuana laws of 35 states]
applies to specific ongoing cases against individuals and businesses
engaged in medical marijuana activity:"
• U.S. v. MAMM
– HOLDING: As long as §538 is in place, the DOJ can only enforce
federal controlled substances laws against MAMM and other
dispensaries if they are not in compliance with California laws.
As the authors of the provision in question, we write to inform you
that this interpretation of our amendment is emphatically
wrong. Rest assured, the purpose of our amendment was to
prevent the Department from wasting its limited law enforcement
resources on prosecutions and asset forfeiture actions against
medical marijuana patients and providers, including businesses that
operate legally under state law. . . . . Even those who argued
against the amendment agreed with the proponents' interpretation
of their amendment. (emphasis added).
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Ending Federal Marijuana Prohibition Act
of 2013
• Introduced in House on February 5, 2013
• Directs the Attorney General to issue a final order that removes
marijuana in any form from all schedules of controlled substances
under the Controlled Substances Act.
• Subjects marijuana to the provisions that apply to intoxicating liquors.
• Grants the FDA the same authority for marijuana as it has for alcohol.
• Transfers functions of DEA relating to marijuana enforcement to ATF.
– Renames: (1) ATF as the Bureau of Alcohol, Tobacco, Marijuana, Firearms and
Explosives; and (2) the Alcohol and Tobacco Tax and Trade Bureau as the Alcohol,
Tobacco, and Marijuana Tax and Trade Bureau.
• Last action: Referred to the Subcommittee on Crime, Terrorism,
Homeland Security, And Investigations. February 28, 2013.
© 2016 by the American Pharmacists Association. All rights reserved.
– Lead Sponsor, Dana Rohrabacher, explained:
The harassment from the [DEA] is something that
should not be tolerated in the land of the free.
Businesspeople who are licensed and certified to
provide doctor recommended medicine within their own
States have seen their businesses locked down, their
assets seized, their customers driven away, and their
financial lives ruined by very, very aggressive and
energetic Federal law enforcers enforcing a law . . . .
(emphasis added).
DEA Authority to Enforce Controlled Substances Act
• U.S. v. MAMM
65
further undermine the DOJ’s position.
61
DEA Authority to Enforce Controlled Substances Act
63
• U.S. v. MAMM
• The comments of lawmakers during the passage of §538
65
64
64
Compassionate Access, Research Expansion,
and Respect States Act of 2015 (S. 683)
• Introduced in Senate March 10, 2015
• Provides that the Controlled Substances Act sections relating to
marihuana shall not apply to any person acting in compliance with
State law relating to the production, possession, distribution,
dispensation, administration, laboratory testing, or delivery of medical
marihuana.”
• Removes marihuana from Schedule I and places it in Schedule II.
• Removes sanctions against banks for providing services to “services
to a marijuana-related legitimate business.”
• Last action: Read twice and referred to the Committee on the
Judiciary on March 10, 2015.
66
66
Respect State Marijuana Laws Act of 2015 (H. R. 1940)
A BILL
To amend the Controlled Substances Act to provide for a new rule regarding the
application of the Act to marihuana, and for other purposes.
1. Short title
This Act may be cited as the Respect State Marijuana Laws Act of 2015.
2. Rule regarding application to marihuana
Part G of the Controlled Substances Act (21 U.S.C. 801 et seq.) is amended by
adding at the end the following:
State Laws
Sec. 710. Rule regarding application to marihuana
Notwithstanding any other provision of law, the provisions of this subchapter
related to marihuana shall not apply to any person acting in compliance with
State laws relating to the production, possession, distribution, dispensation,
administration, or delivery of marihuana.
67
• 24 states and the District of Columbia have passed
legislation or voter initiatives legalizing the possession and
distribution of marijuana for medical purposes under state
or territorial law.
Five states have legalized recreational use
–
–
–
–
68
Medical Marijuana Chronology
Current Status of State Marijuana Laws
•
68
67
• May 1985: Marinol Approved by FDA
• 1991: Jenks v. State, 582 So.2d 676, (Fla.App. 1 Dist. 1991)
(medical necessity defense established by patient with AIDS for
vomiting)
• For further details of chronology, see, ProCon.com—Historical
Timeline
Alaska
Colorado
Oregon
Washington
69
69
State Marijuana Laws
© 2016 by the American Pharmacists Association. All rights reserved.
70
Timeline Showing the Years States and the District of Columbia Passed
Measures Legalizing Medical and Recreational Marijuana under State Law
and the Years DOJ Issued Marijuana Enforcement Policy Guidance
Marijuana Policy Project
71
70
71
72
72
Sources of Information and Laws
Source
Insight into Arguments Pro and Con
Link
• Utah Health and Human Services Interim Committee meetings
National Conference of State
Legislatures
http://www.ncsl.org/research/health/statemedical-marijuana-laws.aspx
GAO Report--STATE MARIJUANA
LEGALIZATION: DOJ Should
Document Its Approach to Monitoring
the Effects of Legalization
http://www.gao.gov/assets/680/674465.pd
Marijuana Policy Project
https://www.mpp.org/states/
ProCon.org
http://medicalmarijuana.procon.org/view.resour
ce.php?resourceID=000881
United States Code
http://uscode.house.gov/
Code of Federal Regulations
http://www.ecfr.gov/cgibin/ECFR?page=browse
DEA Website
http://www.deadiversion.usdoj.gov/Resources.h
tml
provide materials presented by both sides
– May 20, 2015
http://le.utah.gov/asp/interim/Commit.asp?year=2015&com=INTHHS
73
• 3J-The Impact of State Medical Marijuana Legislation on Adolescent
Marijuana Use (JAH; recommended by Sen. Madsen)
• 3K-Medical marijuana opponents? most powerful argument is at odds
with a mountain of research (WAPO Wonkblog; recommended by Sen.
Madsen)
• 3L-Medical Marijuana---Potential Objectives and Issues for Study
• 3M-Medical Marijuana---Legalization Status
• 3N-Medical Marijuana---Selected List of Stakeholders, Interested
Parties, and Other Potential Sources of Information
74
73
74
Insight into Arguments Pro and Con
Insight into Arguments Pro and Con
• Utah Health and Human Services Interim Committee July
• Resources from Utah Health and Human Services Interim
15, 2015
Committee Meeting August 9, 2015
– http://le.utah.gov/asp/interim/Commit.asp?year=2015&com=INTHHS
– 2A-The Endocannabinoid System and Quality Control of Cannabis
Medicines (Marcu)
– 2B-Patient Focused Certification--Regulators Program Guide for
Medical Cannabis (Americans for Safe Access)
– 2C-Marijuana (Fleckenstein)
– 2D-Safety and Toxicology of Cannabinoids (Yurgelun-Todd)
– 2E-Marijuana for Medical Use in Colorado (Gerhardt)
– 2F-Statement on Proposed Medical Marijuana Legislation
(Webster)
• 2A-Consequences of Conflicting Federal and State Laws
(DOPL)
• 2B-Legalization of Medical Marijuana--Three Patient Stories
(Sen Madsen)
• Testimony of Kevin A. Sabet. Ph.D. President, Project SAM
(Smart Approaches to Marijuana)
75
76
75
2016 Legislative Action
2016 Legislative Action
• Utah—Two Competing Bills
• Utah HB0086
– HB 0089
– Broadens medial use of cannabadiol
– Allows an individual with a qualifying illness to register and
possess and use cannabidiol
– Directs the Department of Health to issue a medical cannabidiol
card to a qualified patient or a designated caregiver of a qualified
patient
– Allows cannabadiol facilities
77
© 2016 by the American Pharmacists Association. All rights reserved.
76
77
– Qualifying Illnesses:
•
•
•
•
•
epilepsy;
nausea and vomiting during chemotherapy;
appetite stimulation caused by an HIV or AIDS infection;
muscle spasticity or a movement disorder; and
neuropathic pain conditions as follows:
–
–
–
–
–
–
–
complex regional pain syndrome;
peripheral neuropathy caused by diabetes;
post herpetic neuralgia;
pain related to HIV;
pain related to cancer;
pain occurring after and related to a stroke; and
phantom limb pain.
78
78
2016 Legislative Action
2016 Legislative Action
• Utah SB0073
• Utah SB0076
– Qualifying Illnesses:
– Allows use of whole cannabis, defined as marijuana
– Allows licensing of cannabis facilities
– Qualifying illnesses:
• epilepsy or a similar condition that causes debilitating seizures;
• multiple sclerosis or a similar condition that causes persistent and
debilitating
• muscle spasms;
• post-traumatic stress disorder related to military service; and
• chronic pain in an individual, if a physician determines that the
individual is at risk of becoming chemically dependent on, or
overdosing on, opiate-based pain medication.
– And other conditions approved by a Compassionate Use Committee on a
case-by-case basis
•
•
•
•
acquired immune deficiency syndrome or an autoimmune disorder;
Alzheimer's disease;
amyotrophic lateral sclerosis;
cancer, cachexia, or a similar condition with symptoms that include
physical
• wasting, nausea, or malnutrition associated with chronic disease;
• Crohn's disease or a similar gastrointestinal disorder;
79
State Marijuana Laws
• Colorado
– Colorado:
• November 6, 2012 ballot initiative approved by 55% of voters
• Amendment 64 (“Use and Regulation of Marijuana”) amended
Article XVIII of the Colorado Constitution by adding Section 16
– In the interest of the efficient use of law enforcement
resources, enhancing revenue for public purposes, and
individual freedom, the people of the state of Colorado find
and declare that the use of marijuana should be legal for
persons twenty-one years of age or older and taxed in a
manner similar to alcohol. (emphasis added).
82
82
State Marijuana Laws (Colorado)
• Colorado
– 2000: Amendment 19
• Judge orders medical marijuana placed on the Colorado ballot as
Amendment 20. Voters approve it, 54 percent to 46 percent.
– 2009: explosion of new medical marijuana patient applications.
Cardholders went from 4,800 in 2008 to 108,000 in 2009 — along
with 532 licensed dispensaries — in 2012.
– 2010: Colorado Legislature passes HB10-1284, which legalizes fullscale dispensaries, marijuana cultivation operations and
manufacturers for marijuana edible products. Unique because it
creates both a state regulatory agency and state business licensing:
the Department of Health and Environment for the patients and
caregivers, and dispensary business licensing under the state
Department of Revenue’s Marijuana Enforcement Division.
© 2016 by the American Pharmacists Association. All rights reserved.
– Non-Medical--Residents 21 years old or older can:
• Possess up to 1 ounce of cannabis while traveling
• Gift up to 1 ounce to another adult
• Grow up to 3 immature cannabis plants and 3 mature cannabis
plants
• Non-Residents can:
– Purchase up to ¼ oz. in a single transaction
• Cannot consume “openly or publicly”
81
State Marijuana Laws (Colorado)
83
80
State Marijuana Laws (Colorado)
• Examples of Decriminalization
81
80
79
83
• Colorado: Legalization
– November 6, 2012 ballot initiative approved by 55% of voters
– Amendment 64 (“Use and Regulation of Marijuana”) amended Article
XVIII of the Colorado Constitution by adding Section 16
• In the interest of the efficient use of law enforcement resources,
enhancing revenue for public purposes, and individual freedom,
the people of the state of Colorado find and declare that the use of
marijuana should be legal for persons twenty-one years of age or
older and taxed in a manner similar to alcohol. (emphasis added).
84
84
State Marijuana Laws (Colorado)
Quality Control
• Colorado: Legalization
– Non-Medical--Residents 21 years old or older can:
• Possess up to 1 ounce of cannabis while traveling
• Gift up to 1 ounce to another adult
• Grow up to 3 immature and 3 mature cannabis plants
• Non-Residents can Purchase up to ¼ oz. in a single transaction
• Cannot consume “openly or publicly”
• Cannot travel across state lines while in possession of marijuana
Pot edibles made in washing machine recalled
An edible marijuana maker is taking hear from Denver public health officials for using a washing
machine containing mold to make bubble has, a key ingredient in their edibles
85
• Medical use (11 qualifying chronic uses)
• Confidential registry and identification cards
• No criminal penalties for possession by patients who:
– 18 years old
– Must obtain Registration Certificate
– Marijuana must be grown in Connecticut
– Possess a signed statement from their physician affirming that
he or she suffers from a debilitating condition and that the
"potential benefits of medical use of marijuana would likely
outweigh the health risks.”
• Must be provided by a “dispensary”
• "Licensed dispensary" or "dispensary"means:
– a pharmacist licensed . . . who the Department of Consumer Protection
determines to be qualified to acquire, possess, distribute and dispense
marijuana . . . and who is licensed as a dispensary by the Department of
Consumer Protection . . . .
– An "adequate supply” jointly between patient and the primary
caregiver—cannot exceed 3 mature marijuana plants, 4
immature marijuana plants, and 1 ounce of usable marijuana per
mature plant.
88
88
States in which Marijuana Legislation has
Been Introduced 2016
• Approved conditions:
• Cancer
• Glaucoma
• HIV/AIDS positive
• Chronic or debilitating disease or medical condition or its treatment that
produces:
• cachexia or wasting syndrome
• severe pain
• severe nausea
• seizures, including those characteristic of epilepsy, or severe and
persistent muscle spasms, including those characteristic of multiple
sclerosis or Crohn's disease.
© 2016 by the American Pharmacists Association. All rights reserved.
• Possession Limits:
87
State Marijuana Laws—Medical Use Legal
(Hawaii)
89
86
State Marijuana Laws—Medical Use Legal
(Hawaii)
State Marijuana Laws (Connecticut)
87
86
85
89
Arizona H.B. 2006 and 2007
Would remove criminal liability for small
amounts
Georgia HB 722
Would allow medical use
Hawaii SB 873, SB 383, HB 717)
Would legalize personal use 18 y.o.
Massachusetts (Ballot initiative)
Would legalize personal use 21 y.o.
Illinois HB4276
Would legalize personal use 21 y.o.
Kentucky SB16
Cannabis Freedom Act would legalize
personal use 21 y.o.
Michigan (HB 4877)
Would legalize personal use 21 y.o.
Missouri HJR 57
Proposes a constitutional amendment
legalizing marijuana
90
90
States in which Marijuana Legislation has
Been Introduced 2016
Effects on Adjacent States
• Between a Rock and a
New Hampshire
Would legalize personal use 21 y.o.
New Jersey A 2068
Would legalize personal use 21 y.o.
New Mexico HB 75, SJR 5, SJR 6
Proposes ballot initiative for legalizing
marijuana
New York SB 1747, AB 3089
Would legalize personal use 18 y.o.
Pennsylvania SB 528
Legalize personal use 21 y.o.
Vermont S 95, S 241, H 277
Legalize personal use 21 y.o.
Wisconsin AB 224
Legalize personal use 21 y.o.
Washington D.C. B21-0023
Legalize personal use 21 y.o.
91
91
The Marijuana Civil War—Nebraska &
Oklahoma v. Colorado
High Place: How
Neighboring States
Struggle when Pot
Becomes Legal
92
92
The Marijuana Civil War—Nebraska &
Oklahoma v. Colorado
• “In our constitutional system, the federal government has
preeminent authority to regulate interstate and foreign
commerce, including commerce involving legal and illegal
trafficking in drugs such as marijuana. This authority derives
from the United States Constitution, acts of Congress, including
the Controlled Substances Act . . . and international treaties,
conventions, and protocols to which the United States is
signatory.”
• Nebraska and Oklahoma claim Colorado has “created a
dangerous gap” in the federal drug-control system and
“[m]arijuana flows from this gap into neighboring states,” . . .
“draining their treasuries, and placing stress on their criminal
justice systems.”
93
93
94
94
The Marijuana Civil War--Oklahoma v.
Oklahoma
The Marijuana Civil War--Oklahoma v.
Oklahoma
• Seven Oklahoma legislators publicly criticized that state’s
• “We believe this lawsuit against our sister state has the
attorney general for filing suit to strike down Colorado’s
marijuana law.
• “[M]any of our Constituents want us to consider filing an
amicus brief on behalf of Colorado.”
• “Our primary concerns surround the implications of this lawsuit
for states' rights, the Tenth Amendment, and the ability of states
and citizens to govern themselves as they see fit.”
95
© 2016 by the American Pharmacists Association. All rights reserved.
95
potential, if it were to be successful at the Supreme Court, to
undermine all of those efforts to protect our own state's right to
govern itself under the Tenth Amendment to the U.S.
Constitution. While it may be open to interpretation, we also do
not believe the commerce clause grants the federal government
any power to regulate intrastate trade or marijuana.” (emphasis
added)
• “If the commerce clause could be interpreted so broadly, there is
virtually nothing the federal government could not regulate or
control under the guise of ‘commerce.’“
96
96
The Marijuana Civil War--Oklahoma v.
Oklahoma
• Deep concerns in the lawsuit are “implications for the national
Pharmacokinetics
Smoked vs. Eaten
sovereignty of our entire country. The suit against Colorado
contains multiple references to a series of three United Nations
drug conventions. It even argues flatly that these international
agreements are the equivalent of constitutional federal laws.”
• “The lawsuit also appears to endorse federal commandeering of
state and local resources to enforce federal statutes and
international treaties.”
• “[A]ttempting to undermine the sovereignty of a neighboring
state using the federal courts, even if inadvertently, is [not] a
wise use of Oklahoma's limited state resources.”
97
98
97
98
Medical Marijuana:
Formulations
http://www.leafly.com/explore Accessed 12/23/15
99
100
99
Marijuana Through the Lungs
3 Routes of Administration
• Similar to IV bolus
• Passive diffusion into alveolar
•
•
•
•
LUNGS
Vaporized or
Smoked
Organic material, hash,
hash oil
GUT
Oral Ingestion
Lipophilic, alcoholic,
supercritical fluidic
extracts of plant
material
100
•
SKIN
Topical
Application
•
•
Creams, buccal
tinctures, and
patches made from
plant extracts
capillaries
Bioavailability: 2-56%
Fraction absorbed: 10-20%
Rapid onset (sec-min)
Maximal onset 30 minutes and
lasting 2-3 hours
Metabolism in liver, lung, and
brain
Elimination t½ = 20 hrs (2-13
days)
Elimination primarily via feces
(65%) and urine (20%)
Clin J Pain 2013;29:162-71. Brit J
Clin Pharm 2009;67(1):5-21.
Iran J Psychiatry. 2012;7(4):149–156.
Clin Pharmacol Ther 2007;82:572-8.
Pharmacol Rev 1986 Mar;38(1):21-43.
Can easily
titrate to
desired effect
Chem Biodivers. 2007;4(8):1770-804.
Clin Pharmacol Ther 1980 Sep;28(3):409-16
Clin Pharmacol Ther 2007;82:572-8. Clin J Pain 2013;29:162-71.
101
© 2016 by the American Pharmacists Association. All rights reserved.
101
102
Marijuana Through the Gut
• Variable absorption
• Bioavailability ranges 420%
• Onset: 30 minutes-2 hours
• Duration: 5-8 hours
• Metabolized primarily in the
liver
• 11-hydroxy-THC
• Elimination t½ = 20-30 hrs
• High inter- and intra-patient
variability
Pharmacotherapy 2013;33:195-209
Brit J Clin Pharm 2009;67(1):5-21
Clin Pharmacol Ther 1980 Sep;28(3):409-16
State Marijuana Laws (Colorado)
Delayed and erratic drug
delivery – more difficult to titrate
103
• Driving
– Most states have zero tolerance for marijuana (THC) in the blood
– The fact that a person charged with drugged driving is entitled to
use the legal or medical use of marijuana does not constitute a
defense against any charge of driving under the influence.
Colorado Revised Stat.§42-4-1301(1)(e).
– Presumptive impairment 5 ng/ml limit
• But, woman with 19 ng/ml THC Level Acquitted:
– http://kdvr.com/2015/07/17/driver-acquitted-of-marijuanadui-despite-high-blood-test/
104
103
104
Pharmacodynamics in Action:
Oral Formulations
Driving
• New Technology to detect THC levels
– http://kdvr.com/2016/01/26/colorado-state-troopers-testingmarijuana-dui-devices/
• Marijuana and Driving Q&A
100 mg THC
– https://www.codot.gov/safety/alcohol-and-impaireddriving/druggeddriving/marijuana-and-driving
85 mg THC
• Traffic Stop to Evaluate Marijuana Impaired Driving
– http://www.thecannabist.co/2014/09/12/video-see-stoned-drivingtest-colorado-state-patrol/19567/
10 mg/unit
105
105
300 mg THC
175 mg THC
106
225 mg THC
106
State Marijuana Laws (Colorado)
New amendments limit THC content to 10 mg per unit.
Up to 100 mg per package.
State Marijuana Laws (Colorado)
Edibles: A growing business
107
© 2016 by the American Pharmacists Association. All rights reserved.
107
108
108
Key Point
Marijuana Through the Mucosa
• Onset: 15-40 minutes
• Duration: 45 minutes-2 hours
• May have inter- and intra-patient variability
• Plasma levels of THC and other cannabinoids are lower
compared with the levels achieved following inhalation of
cannabinoids at a similar dose (nabiximols)
• Metabolized in the liver
• Elimination via feces (65%) and urine (35%)
Given the wide variety of formulations available, it is
important to consider various pharmacokinetic and
pharmacodynamic parameters.
A patient-determined, self-titrated dosing model should be
used. The most effective and tolerable formulation and dose
will vary based on body type, weight, and condition.
Providers need to step into a shared decision making model
with patients.
Ther Adv Neurol Disorders. 2012;5(5):255-66.
http://www.medicines.org.uk/emc/medicine/23262#PHARMACOKINETIC_PROPS
109
110
109
110
MMJ Registrants in CO and OR:
Qualifying Conditions
Therapeutic Effectiveness of MMJ
OREGON
CONDITION
NUMBER (%)
Severe pain
74,432 (97%)
Muscle spasms
22,587 (29.4%)
Nausea
10,975 (14.3%)
PTSD
5,433 (7.1%)
Cancer
4,541 (5.9%)
Seizures
2,153 (2.8%)
Glaucoma
1,215 (1.6%)
Cachexia
1,176 (1.5%)
HIV/AIDS
824 (1.1%)
Degenerative
neurologic condition
91 (<1%)
TOTAL
76,723
https://www.colorado.gov/pacific/sites/default/files/09_2015_MMRreport.pdf Accessed 12/23/15.
https://public.health.oregon.gov/DiseasesConditions/ChronicDisease/MedicalMarijuanaProgram/Pages/data.aspx
111
I.
“HIGHEST” level of evidence
Blog
Case control study
Case report
Case series
Cohort study
Meta-analysis
My opinion
Randomized controlled
trial
Review article
112
Inhaled Cannabis for Neuropathic Pain:
Meta-Analysis of Individual Data
How Should MMJ Be Studied?
A.
B.
C.
D.
E.
F.
G.
H.
112
111
• Synthesizes the individual participants' original data obtained from the
studies' principal investigators
• Five randomized controlled trials evaluating inhaled cannabis
• Compared proportion of patients experiencing >30% clinical
improvement in chronic neuropathic pain assessed with a continuous
patient-reported instrument (e.g., visual analog scale) at baseline and
after inhaled cannabis
RESULTS
• 178 patients with 405 observed responses
• Estimated OR (CRI) for >30% ↓ in pain score: 3.22 (1.59-7.24)
• Number needed to treat (CRI): 5.55 (3.35-13.7)
“LOWEST” level of evidence
113
© 2016 by the American Pharmacists Association. All rights reserved.
Note: gabapentin NNT 5.9 (4.6-8.3) for diabetic neuropathy
J Pain 2015;16:1221-32. Cochrane Database of
Systematic Reviews 2014, Issue 4. Art. No.: CD007938.
113
114
114
Crossover Study: Low-dose Vaporized Cannabis
• Objective: evaluate analgesic
efficacy in patients with
neuropathic pain despite
traditional treatments
• Visual analog scale (0-100)
• 39 patients with previous
cannabis exposure
– 28 male/11 female
– Avg age 50 years
• Vaporized cannabis
– Medium-dose (3.53%)
– Low-dose (1.29%)
– Placebo
J Pain 2013;14:136-48
MMJ in Painful HIV-Associated Sensory
Neuropathy: Systematic Review and Meta-Analysis
INHALED CANNABIS
Number of
episodes
111
≥30% ↓ in VAS
Placebo
Low-dose
Med-dose
Number [% (95%CI)}
10/38 [26% (15-42%)]
21/37 [57% (41-71%)]
22/36 [61% 45-75%)]
• Objective: evaluate clinical
Statistical significance
P vs Low: p=0.0069
P vs Med: p=0.0023
Low vs Med: p=0.7
NNT: Low
3.2
NNT: Med
2.9
115
or post-surgical
neuropathic pain
• Cannabis 25 mg at 0%,
2.5%, 6%, and 9.4% THC
smoked 3x/day
• Four 14-day periods in
crossover trial
• Primary outcome: pain
intensity (11-item scale)
RESULTS
•
•
122
≥30%
improvement in
VAS
31/61
≥50%
improvement in
VAS
15/61
RR (95% CI)
2.38 (1.38 to 4.10)
NNT (95% CI)
3.38 (2.19 to 7.50)
116
115
• Pain intensity
•
SMOKED CANNABIS
Number of
episodes
*NNT for capsaicin 8% = 6.46 (3.86-19.69)
Smoked Cannabis for Chronic Neuropathic Pain
• 21 adults post-traumatic
effectiveness of various
analgesics
• Total of 14 trials evaluated
• Smoked cannabis 1-8%
and capsaicin 8% found to
be effective
– 9.4%: score = 5.4
– 0%: score = 6.1
– (p=0.023; difference 0.7, 95% CI 0.021.4)
Sleep (more drowsiness, getting to sleep
more easily, faster, and with less
wakefulness)
– 9.4% vs 0%: p<0.05
Anxiety and depression improved (EQ5D)
– 9.4% vs 0%: p<0.05
Adverse events
– 248 mild; 6 moderate (fall, ↑pain,
numbness, drowsiness, pneumonia
CMAJ 2010;182:E694-701.
116
Systematic Review: Efficacy and Safety of Medical Marijuana in
Selected Neurologic Disorders
Report of the Guideline Development Subcommittee of the
American Academy of Neurology
In Patients with Multiple Sclerosis
Condition
Effective
Possibly effective
Spasticity
OCE
Nabiximols, THC
Central pain or
painful spasms
OCE
Nabiximols, THC
Nabiximols
Urinary
dysfunction
Tremor
Probably or possibly
ineffective
THC, OCE
THC, OCE, nabiximols
“The risks and benefits of medical marijuana should be weighed carefully.”
“Comparative effectiveness of medical marijuana vs other therapies is
unknown for these indications.”
Neurology. 2014 Apr 29;82(17):1556-63
117
118
117
Psychiatric Implications
Pediatric Epilepsy: AES Annual Meeting 2015
•
•
•
•
• Acute cannabis psychosis
261 children (average age 11 years)
Severe epilepsy not responding to other treatments
Epidiolex given in increasing doses with other AEDs (avg=3)
After 3 months of treatment
–
–
–
–
–
45% lower frequency of seizures
47% experienced ≥50% reduction in seizures
9% seizure-free
Dravet syndrome patients: 62% reduction in seizures, 13% seizure free
Lennox-Gastaut patients: 71% reduction in atonic seizures
• Adverse effects (>10%)
– Sleepiness, diarrhea, fatigue (4% discontinued treatment)
• Serious adverse effects: 5% treatment-related
– Altered liver enzymes, status epileptus, diarrhea and others
• Lack of efficacy caused 12% withdrawal
http://www.medicalnewstoday.com/articles/303725.php Accessed 12/23/15
119
© 2016 by the American Pharmacists Association. All rights reserved.
118
119
–
–
–
–
Very large dose of cannabinoid botanical consumed
Typically through oral ingestion (concentrated preparation)
Agitation, confusion, sedation
Self-limiting and generally disappears after metabolism/excretion
• Acute schizophreniform reaction
– Young adults under stress and have other vulnerabilities to
schizophreniform illness
– Early and heavy cannabis exposure may increase the risk of
developing a psychotic disorder such as schizophrenia
– Carefully monitor or avoid in early teens or preteens with
preexisting symptoms of mental illness or patients with significant
family or personal history of mental illness
J Psychiatr Res 2013 Apr;47(4):438-44 J Clin Psychiatry 2012;73:1463-8
Clin J Pain 2013;29:164-71. http://www.health.harvard.edu/blog/teens-who-smoke-pot-at-risk-for-later-schizophreniapsychosis-201103071676. Accessed 12/23/15
120
120
Marijuana Exposure in Childhood and Adolescence
• 3Ds: Dependence – Depression – Dysfunction
• Dunedin Study (Meier 2012)
–
–
–
–
Over 1000 individuals followed from birth (‘72/’73) to 38 years
Cannabis use ascertained at 18, 21, 26, 32, and 38 years
Neuropsychological testing at 13 and 38 years
Results for persistent adolescent users:
• Greater decline in IQ (~6 IQ points)
• Greater neuropsychological impairment
– Executive functioning and processing speed
– Informants reported observing significantly more attention
and memory problems
• Conclusion:
Cannabis Treatment for Chronic Pain
Systematic Review and Meta-Analysis
OUTCOME
• 18 double-blind RCTs
• Synthetic derivatives
included
• Efficacy outcome: “intensity
of pain” by VAS
• Harms: number of adverse
events
• Concluded moderate
efficacy, but risks may be
greater than benefit
– Neurotoxic effects of cannabis on the adolescent brain
4.11 (1.33, 12.72)
Dysphoria
2.56 (0.66, 9.92)
Blurred vision
8.34 (4.63, 15.03)
Tinnitus
2.18 (0.93, 5.11)
Disorientation/Confusion
3.24 (1.51, 6.97)
Dissociation/
Acute psychosis
3.18 (0.89, 11.33)
Speech disorders
4.13 (2.08, 8.20)
Ataxia, muscle twitching
3.84 (2.49, 5.92)
Numbness
3.98 (1.87, 8.49)
Impaired memory
3.45 (1.19, 9.98)
Attention disturbances
5.12 (2.34, 11.21)
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121
Treatment of Chronic Non-Cancer Pain:
Systematic Review of Randomized Trials
Cannabinoid
-0.61 (-0.84, -0.37)
Euphoria
Pain Medicine 2009; 10(8):1353-68)
 Proc Natl Acad Sci U S A. 2012;109(40):E2657-64.
121
OR (95% CI)
Intensity of pain
122
Research Gaps
• CLINICAL
Overall result
Smoked cannabis
(n=4)
All trials found positive effect by improving neuropathic pain vs
placebo with no serious adverse effects.
Oromucosal
extracts (n=7)
6/7 trials demonstrated positive analgesic effects for neuropathic
pain, RA, mixed chronic pain. In one trial evaluating RA, significant
decrease in disease activity (28 joint disease activity score).
Nabilone (n=4)
Three showed significant analgesic effect in spinal pain,
fibromyalgia, and spasticity related pain vs placebo. One showed
similar effect in neuropathic pain vs dihydrocodeine.
Dronabinol (n=2)
Significant reduction in central pain (MS) vs placebo.
Significantly greater analgesia vs placebo for mixed chronic pain
on opioids.
–
–
–
–
–
Specific medical conditions
Specific cannabinoid effects
Varied formulation and dose-related effects
Patient participation (including naïve and regular users)
Methodology/design
• FEDERAL
– Schedule I drug
– Difficult to conduct tightly controlled studies using
strains/forms/doses consumed in “real world”
– Unable to provide cannabis with substantial levels of CBD
Ajulemic acid led to significant improvement in neuropathic pain
THC-11-oic acid
analogue - CT-3 or intensity at 3 hours, but no difference at 8 hours compared with
ajulemic acid (n=1) placebo.
Br J Clin Pharmacol 2011;72(5):735-44
123
• Report as much as possible about beneficial and harmful effects
• FEDERAL
– Investigator must secure a Schedule I research registration from
the DEA and often a Schedule I research license from the statecontrolled drug agency
– FDA assesses research and data from clinical studies where
research is initiated by either investigator or a pharmaceutical
company
– Investigational new drug application with 1+ protocols must be
presented and allowed by the FDA
– Expanded access may also be allowed for seriously ill patients
– “Differential scheduling” is possible (e.g., dronabinol – synthetic
THC – Schedule III)
125
© 2016 by the American Pharmacists Association. All rights reserved.
124
Future Research Improvements
Research Gaps
J Clin Pharmacol 2015;55:839-41.
Clinical Researcher 2015; Apr:58-63.
124
123
125
in medical conditions
Report as much as possible about strains of cannabis
Concentration of cannabinoids in plant
Concentration of cannabinoids in blood of participants
Do not equate effects of cannabis in human samples with effects
of synthetic THC and CBD
• Plant has complex set of interactions with cannabinoids and
terpenes (among other components)
• Need to study strains used in “real world”
• Challenges can be overcome with high-quality clinical research
by trained individuals
•
•
•
•
British Journal of Pharmacology. 2011;163:1344–1364.
J Clin Pharmacol 2015;55:839-41.
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126
Other Interesting Clinical Findings
• PTSD: cannabis used more frequently for sleep and coping
– Drug and Alcohol Dependence 2014;136:162–5
– J Psychoactive Drugs 2014;46:73-7
Conclusions
• The endocannabinoid system, including CB1 and CB2
receptors, is the key target for exogenous cannabinoids.
• IBD: improved pain and diarrheal symptoms
• Psychoactive effects of marijuana related to THC, but other
– Inflamm Bowel Dis 2014;20:472–80
– Inflamm Bowel Dis 2013;19:2809–14
– Dig Dis 2014;32:468-74
cannabinoids involved with other therapeutic effects
• Many different formulations and variable doses available in “real
world” setting; should be individualized
• Pediatric treatment-resistant epilepsy: parental reports
• Clinical studies indicate MMJ may have a role in patients with
– Epilepsy Behav 2015;47:138-41
– Epilepsy Behav 2015;45:49-52
– Epilepsy Behav 2013;29:574-7
neuropathic pain and seizures refractory to other treatments.
• Providers should be aware of potential drug interactions and
other patient safety issues
• Migraine
– Pharmacotherapy 2016;article online (DOI: 10.1002/phar.1673)
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Marijuana and Employment
• State laws vary in their protection of workers
Employment and Other Legal
Issues
– Examples of states that provide some protection:
• Arizona—No discrimination based on status as registered
qualified patient
• Unless an employer would lose a monetary or licensing-related
benefit under federal law, an employer may not discriminate
against a person in hiring, termination or imposing any term or
condition of employment or otherwise penalize a person based
upon either:
1. The person's status as a cardholder.
2. A registered qualifying patient's positive drug test for marijuana
components or metabolites, unless the patient used, possessed or was
impaired by marijuana on the premises of the place of employment or
during the hours of employment.
A.R.S.§ 036-2813 B
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130
129
Marijuana and Employment
130
Marijuana and Employment
• Arizona Continued
• Nevada
– Employers are not required to:
• Allow marijuana use at work or
• Allow any employee to work under the influence of marijuana.
– But, a registered qualifying patient is not under the
influence solely because metabolites or components of
marijuana are present in insufficient amounts to cause
impairment. (A.R.S. § 36-2814 A.3.)
– Cannot undertake any task under the influence of marijuana that
would constitute negligence or professional malpractice. (A.R.S. §
36-2802(a))
131
© 2016 by the American Pharmacists Association. All rights reserved.
131
– An employer does not have to allow medical use of marijuana in
the workplace.
– An employer does not have to modify the job or working
conditions of a person who engages in the medical use of
marijuana that are based upon the reasonable business
purposes of the employer.
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132
Marijuana and Employment
Marijuana and Employment (Cases)
• Braska v. Challenge Mfg., Nos. 313932, 315441, 318344,
Nevada continued
• But an employer must attempt to make reasonable
accommodations for the medical needs of an employee who
engages in the medical use of marijuana if the employee holds
a valid registry identification card, if such reasonable
accommodation would not:
– Pose a threat of harm or danger to persons or property or
impose an undue hardship on the employer; or
– Prohibit the employee from fulfilling any and all of his or her
job responsibilities.
NRS 453A.800
133
– Held that employees who used marijuana in compliance with the
Michigan Medical Marijuana Act (“MMMA”) and who tested positive for
marijuana at workplace drug screen could collect unemployment
benefits.
– Reasoned that the MMMA created a broad immunity because under
the law, a registered qualified patient “shall not be subject to arrest,
prosecution, or penalty in any manner, or denied any right or privilege
. . . . for medical use of marijuana in accordance with this act.”
– Denial of unemployment benefits fell within the broad term “penalty.”
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133
Marijuana and Employment (Cases)
• Ross v. Ragingwire Telecommunications, 70 Cal. Rptr. 3d 382
(Cal. 2008)
– Held that a medical marijuana user who was fired as a result of a
positive drug test did not have a claim for disability-based
discrimination or for wrongful termination in violation of public policy.
• Emerald Steel Fabricators, Inc. v. Bureau of Labor and
Industries, 230 P.3d 518 (Or. 2010)
– Held that an employer that fired an employee who had a valid
registration identification card for marijuana use for a debilitating
condition did not violate Oregon law that prohibited discrimination
based on disability.
– Federal law that makes marijuana use illegal preempts Oregon law
that allows medical marijuana use. Therefore the employee’s use of
marijuana was illegal.
135
Mich. Ct. App., October 23, 2014.
Marijuana and Employment (Cases)
• Coats v. Dish Network, 350 P. 3d, 849 (Colo. June 15,
2015)
– RELIEF SOUGHT: Terminated employee appealed dismissal of
his suit against employer alleging that his termination was based
on his “lawful” state-licensed use of medical marijuana.
– ISSUE: Was a quadriplegic’s use of medical marijuana under
Colorado’s Medical Marijuana Amendment lawful under Colorado’s
law that prohibits employment discrimination for “lawful” activities
(Colo. Rev. Stat. §24-34-402.5)?
136
135
Marijuana and Employment (Cases)
• Coats v. Dish Network
134
136
Marijuana and Employment (Cases)
• Casias v. Wal-Mart Stores, Inc., 695 F.3d 428 (6th Cir.
– HOLDING: The Colorado Supreme Court affirmed because the
employer did not terminate plaintiff for a “lawful activity” (see §2434-402.5). The court reasoned that marijuana use is illegal under
federal law and nothing in §24-34-402.5 limited the term “lawful”
to state law. The term was used in its general unrestricted sense,
indicating that a “lawful” activity is one that complies with all state
and federal laws.
• The U.S. District Court for the District of Colorado relied on Coats to
conclude that termination of an employee who tested positive for
cannabinoids was not discriminatory because use of marijuana is
illegal under federal law and therefore and “illegal activity.”
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© 2016 by the American Pharmacists Association. All rights reserved.
137
2012)
– Employee who had been diagnosed with sinus cancer and an
inoperable brain tumor used medical marijuana in compliance with
Michigan law. Wal-Mart terminated him after the employee failed a
drug test.
– The MMMA prohibited “any civil penalty or disciplinary action by a
business” against a registered qualified patient “by a business.”
– The court held that in the MMMA the term “business” did not mean
private business, but meant licensing board. Thus, the MMMA did
not regulate private employers.
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138
Other Legal Issues
Property Law Issues
• Banking laws have created a cash and carry marijuana
industry, see, Criminal Money Laundering Law (18 USC §
1956)
• Tax: Illegal income is taxable, but 26 USC § 280E prohibits
deductions business trafficking in Schedule I or II controlled
substances.
• Intellectual Property: Federal law prohibits trademark protection for
• Landlords have to be cautious about illegal uses of rented
premises
– Could landlord be prosecuted under federal law for possession or
distribution?
– Could landlord be responsible under state laws if tenant is
apparently lawful, but in fact is not complying with state marijuana
laws?
marijuana products and services that violate federal law (e.g.,
Cannabis Farmers Market rejected by USPTO)
• Property Law: Banks don’t want to lend money for property used to
commit federal felony
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139
1. Which of the following forms of marijuana has the
Ethics—Conflicts of Interest
slowest onset of action?
A.
B.
C.
D.
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141
Intravenous
Inhaled
Oral
Buccal
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142
3. Which is true about a recent federal court case
2. Which of the following is the most common
reason for MMJ use in Colorado?
A.
B.
C.
D.
E.
F.
140
addressing the DOJ’s (and DEA’s) ability to enforce
federal controlled substances laws?
A. The court ruled the DEA cannot impose penalties or shut
Cancer
Epilepsy
Glaucoma
Muscle spasms
Nausea
Pain
down dispensaries acting lawfully under state law.
B. The court ruled the Supremacy Clause of the U.S.
Constitution allows the DEA to arrest marijuana dispensers
because marijuana is a schedule I substance.
C. The court ruled pharmacists were permitted to be involved in
marijuana dispensaries because they were acting lawfully
under state law.
D. The court ruled owners of dispensaries could be arrested
because of the quantity of marijuana they possessed, but
patients could not be arrested.
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© 2016 by the American Pharmacists Association. All rights reserved.
143
144
144
4. Which of the following is NOT true
about federal cannabis law?
5. Which of the following is true?
A. Marinol (Dronabinol) capsules are available for commercial
A. Pharmacists should never ask patients if they are using
B.
C.
D.
E.
use.
Smoked cannabis is a C-I controlled substance.
Pharmacies may not dispense C-I controlled substances.
The DEA may not enforce its laws to prevent states from
implementing their own state laws
A series of memoranda from the DOJ prohibit the DEA from
enforcing federal marijuana laws in states where marijuana is
legal for medical use.
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Questions?
Laura M. Borgelt, PharmD, FCCP, BCPS, NCMP
Associate Dean for Administration and Operations
Professor, Departments of Clinical Pharmacy and Family Medicine
Skaggs School of Pharmacy and Pharmaceutical Sciences
University of Colorado Anschutz Medical Campus
303-724-2650
[email protected]
William J. Stilling, B.S. Pharm., M.S., J.D.
Chair, Health and Life Sciences Practice Group
Parsons Behle & Latimer
Salt Lake City, UT
801-536-6765
[email protected]
147
© 2016 by the American Pharmacists Association. All rights reserved.
147
marijuana or taking illicit drugs
B. Pharmacists should never put information about patient’s
marijuana use in the patient profile
C. Pharmacists should counsel patients never to use marijuana
D. Pharmacists should counsel patients about known drug-drug
interactions with marijuana
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