The Evolution of State Marijuana, CBD, and Hemp LawsJacquelyn Bainbridge, PharmD, FCCP, MSCS
ProfessorUniversity of Colorado | Anschutz Medical Campus
Skaggs School of Pharmacy and Pharmaceutical Sciences & Department of Neurology
Disclosures
Dr. Bainbridge has two research grants funded by Colorado Department of Public Health and Environment (CDPHE)
Dr. Bainbridge is involved in one research grant funded by Zynerba Pharmaceuticals
Cannabis & Its CompoundsBackground
Cannabis Cannabis: The plant Hemp: Stems, stalks and roots
Contains a higher concentration of CBD Contains <0.3% of THC
Marijuana: Seeds, leaves and flowers Contains a higher concentration of THC, 1-5%
Cannabis contains over 400 compounds Over 100 cannabinoids have been isolated
The predominant cannabinoids are THC and CBD Cannabis is separated into sativa and indica strains
Due to cross-breeding, they have no generalizable characteristics
First documented date of cannabis use for medicinal purposes was in 400 A.D. Cannabis was mentioned in the USP in 1850
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Borgelt LM, Franson KL, Nussbaum AM, Wang GS. Pharmacotherapy. 2013
Differences between Hemp and Marijuana5
Statutory Definition “the plant Cannabis sativa L. and any part of the plant...whether growing or not, with a delta-9 tetrahydrocannabinol concentration of not more than 0.3% on a dry weight basis.”1
“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”2
● Does not include mature stalks● Does not include fiber, oil, or cake from the seed● Does not include sterilized seed incapable of
germination
Psychoactive Properties
Non-psychotropic Psychotropic
Threshold for Psychoactive Compounds
No more than 0.3% delta-9 THC on a dry weight basis
No THC threshold specified
Primary Federal Agencies with Regulatory Oversight
U.S. Department of Agriculture (USDA)Food and Drug Administration (FDA)
U.S. Drug Enforcement Administration (DEA)Food and Drug Administration (FDA)
Hemp Marijuana
1. 2018 Farm Bill. P.L. 115-334, §101132. Federal Food, Drug, and Cosmetic Act. 21 U.S.C. §802(16).
Cannabinoids: Delta-9-tetrahydrocannabinol (THC)The major component that causes the “high” “euphoria” Beneficial effects
Helpful in preventing nausea and vomiting due to cancer chemotherapy Decreases muscle spasticity Increases pain tolerance
Adverse effects Short term:
Memory loss, loss of time, impaired coordination, altered thinking, panic, delusions & hallucinations, paranoia and psychosis
Long term: Addiction (9% overall), altered brain development*, diminished life
satisfaction and achievement*, cognitive impairment (lower IQ)*, symptoms of chronic bronchitis, increased risk of chronic psychosis disorders, and poor educational outcome.
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N Engl J Med 2014; 370:2219-27 *Effect is strongly associated with initial marijuana use early in adolescence
Cannabinoids: Cannabidiol (CBD)
A major non-psychotropic component of cannabis “no high” no euphoria Beneficial effects
No known psychiatric effects No effects on vital signs or mood Shown to decrease seizure frequency Enhance the activity of the endogenous cannabinoid (anandamide)
Adverse effects CNS: Somnolence, fatigue and convulsion GI: Decreased appetite and diarrhea May increase risk of infection
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The Endocannabinoid System The human body naturally produces
endocannabinoids which is responsible for maintaining homeostasis (balance) Anandamide (2-AG)→ natural
cannabinoid found in the body
Endocannabinoids bind to CB1 and CB2 receptors CB1 receptors are found primarily in the
central and peripheral nervous system CB2 receptors are found primarily in the
immune system and peripheral tissues
http://norml.org/library/item/introduction‐to‐the‐endocannabinoid‐system Accessed 3/2/15 Frontiers in Pharmacology 2014;5:Article 37. https://satimedusa.com/pages/what-is-the-endocannabinoid-system
Regulatory Effect of Cannabinoids at the CB1 Receptor
Pertwee RG. Br J Pharmacology. 2008
1. Inhibition of adenylyl cyclase activity
2. Alter second messenger systems so CA++ influx is inhibited
Neuromodulation by anandamide is particularly relevant to modulation of GLU (shown), Ach, GABA, DA, NE
Functional Effects of Anandamide on the CB receptors
http://norml.org/library/item/introduction‐to‐the‐endocannabinoid‐system Accessed 3/2/15 Frontiers in Pharmacology 2014;5:Article 37. https://satimedusa.com/pages/what-is-the-endocannabinoid-system
Structure THC effect CBD effectNeocortex Altered thinking, judgement Delayed onset time to intoxication with THC
Basal ganglia Slowed reaction time Reduced psychomotor abnormalities from THC
Hypothalamus ↑ appetite No to little effect on appetite
Amygdala Panic, paranoia Decrease THC induced anxiety
Nucleus accumbens Euphoria Attenuated THC induced euphoria
Hippocampus Impaired memory Attenuated THC induced memory effects
Cerebellum Impaired coordination Reduced coordination abnormalities from THC
Brain stem Anti-nausea effects
Hippocampus, forebrain Anti-epileptic effects ? Anti-epileptic effects for certain populations
Spinal cord Altered pain sensitivity TRPV reduction in pain
1985
1992
1996
Cannabis Activity At CB1 Receptors
Dose-response effects of CBD not established• Low dose < 300 mg inconsistent effects• Typical response can be seen at 600mg
THC Dosing Is Known, But Not Known For Other CBs
Typical “effective” dosing of inhaled THC Low dose < 7 mgMedium dose = 7 – 18 mgHigh dose > 18 mg Known tolerance to THC down regulation of CB1 receptors, and G-protein
activationHigh probability of tolerance with chronic use, and low with intermittent Chronic = daily for a week, intermittent = weekly
L Zuurman, et al. Br J Clinical Pharmacology. 2008
Cannabis & Its UseMedical applications of cannabisFDA approved cannabis products
Approved Medical Conditions for Cannabis Use 14
Approved Medical Conditions for Cannabis Use15
Approved Medical Conditions
Current legislation is misleading
Cannabis may alleviate symptoms but not actually treat the diseaseMS, cancer, HIV/AIDS, hepatitis C, Crohn’s and Alzheimer’s disease
Do our patients/consumers know the difference?
FDA Approved Products Marinol® /Syndros® (dronabinol) FDA approved in 1985 A synthetic delta-9-tetrahydrocannabinol (THC) Schedule III Used for:
Anorexia in patients with AIDS Nausea and vomiting associated with cancer chemotherapy
Epidiolex® (cannabidiol) FDA approved in June 2018 A plant-derived CBD Schedule V The first FDA approved cannabinoid prescription drug Used for:
Lennox-Gastaut syndrome Dravet syndrome
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Marinol (dronabinol) [package insert]. North Chicago, IL; AbbVie Inc; 2017Syndros (dronabinol) [package insert]. Chandler, AZ; Insys Therapeutics; 2016.Epidiolex (cannabidiol) [package insert]. Carlsbad, CA; Greenwich Biosciences Inc. 2018.
Other ProductsCesamet ® (Nabilone) FDA approved in 2006 A synthetic cannabinoid Schedule II Used for:
Nausea and vomiting for cancer related chemotherapy
Sativex ® (THC and CBD) Licensed for use in the UK Not FDA approved Used for:
Multiple sclerosis related spasticity
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Sativex (THC and CBD) [package insert]. Cambridge, UK; GW Pharmaceuticals; 2016
Cannabis & Its RisksRisks associated with cannabis use
Impact on the brain & neuropsychological functioning
Lifetime Addiction Risk with Use20
Hall and Degenhardt. Lancet. 2009 Strahny A. CBHSQ Report. 2013
Brain Development in Adolescence
Limbic region Immediate rewards Impulsive behavior
Cortex Long-term gain Thoughtful behavior
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http://erichengelhardt.net/neuro-facts.html
The Reward Pathway22
NIDA (http://drugabuse.gov/sciencefair/)
Study comparing the acute effects of inhaled cannabis in male adolescents (16-17 years old) and adults (24-48 years old).
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Adolescents▪ Felt less “stoned”▪ Dry mouth▪ No difference in alertness or anxiety▪ Fewer psychotomimetic symptoms▪ Impaired response inhibition▪ Lacked satiety and wanted more cannabis
Adults▪ More anxious▪ Increased dry mouth▪ Less alert▪ Greater cognitive impairment▪ Showed satiety, did not want more cannabis
Mokrysz C, Freeman TP, Korkki S, Griffiths K, Curran HV. Are adolescents more vulnerable to the harmful effects of cannabis than adults? A placebo-controlled study in human males. Translational Psychiatry. 2016;6(11). doi:10.1038/tp.2016.225.
Effect on Neuropsychological Functioning Persistent cannabis users (>20 years) show neuropsychological decline from
childhood to midlife
Led to impairment of learning, memory and executive functions (paying attention, organizing, planning, starting tasks, regulating emotions)
Cessation of cannabis did not restore the loss in neuropsychological functioning - this finding is suggestive of the neurotoxic effects of marijuana in adolescents.
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Never User IQ: 100.64
Regular User IQ: 90.77
Acute Illness Associated with Cannabis Use After marijuana legalization in Colorado in 2012, ER visits linked to cannabis use
tripled over the next 5 years at University of Colorado Hospital
People eating marijuana products were more likely to present to the ER with severe panic attacks or other sudden mental disorders.
Risks of hospitalization with edibles may be increased due to the delayed “high,” which may not be felt for 2-3 hours after ingesting and people redose the drug
Inhaled marijuana causes a higher rate of hospitalizations due to severe vomiting associated with heavy cannabis use
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Rules & Regulations of CannabisScheduling of cannabisFederal laws & policy
Federal agencies
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https://medicalmarijuana.procon.org/view.resource.php?resourceID=000881
Colorado
Amendment 20 passed in November 2010 Allowed for the medical use of marijuana
Amendment 64 passed in November 2012 Allowed for the recreational use of marijuana
The Colorado Department of Public Health and Environment (CDPHE) approved funding for the first two clinical investigations involving cannabis at the Anschutz Medical Campus
As of 2018, Colorado is 1 of 8 states with a medical cannabis research program
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Heike, Newman. Food and Drug Law Journal Symposium Spotlight: Cannabis Clinical Investigations in Colorado 2019 . FDLI. 2019; 18-25.
DEA Drug Scheduling29
Schedule I ● Substances/chemicals defined as drugs with no currently accepted medical use● High potential for abuse● Examples: Marijuana, heroin, LSD, ecstasy, peyote
Schedule II ● Drugs with a high potential for abuse● Can potentially lead to severe psychological or physical dependence● Examples: Nabilone, hydrocodone, methadone, methamphetamine, cocaine
Schedule III ● Drugs with a moderate to low potential for physical and psychological dependence● Examples: Dronabinol, Tylenol with codeine, anabolic steroids, testosterone
Schedule IV ● Drugs with a low potential for abuse and low risk of dependence● Examples: Tramadol, xanax, ambien, valium
Schedule V ● Drugs with lower potential for abuse than Schedule IV● Generally used for antidiarrheal, antitussive, and analgesic purposes.● Examples: Cannabidiol -Epidiolex®, lyrica, lomotil
https://www.dea.gov/drug-scheduling
Status of Marijuana at the Federal Level
Controlled Substances Act of 1970 Marijuana was listed as a Schedule I substance due to:
No currently accepted medical use High potential for abuse
2018 Farm Bill Hemp removed from Schedule I controlled substances
Legalized cultivation, possession, sale and distribution of hemp plant State authority to regulate and limit production and sale, but not transportation
or shipment CBD from hemp plant must contain less than 0.3% of THC
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Executive Summary of New Hemp Authorities. USDA. https://www.ams.usda.gov/sites/default/files/HempExecSumandLegalOpinion.pdf
Drug Enforcement Agency (DEA)
DEA requires special registration for the investigator and the site when using cannabis for research
Oversees the Schedule I controlled substance licenses Establishes the yearly cannabis production quota for NIDA In 2016, the DEA announced that they will increase the number of entities
allowed to grow cannabis for research in the US. 25 cannabis growers submitted their manufacturing applications Applications are still pending
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Throckmorton, Douglas. FDA Regulation of Marijuana: Past Actions, Future Plans. ICSB/ASP Joint Meeting. Presented on: April 12, 2016.Heike, Newman. Food and Drug Law Journal Symposium Spotlight: Cannabis Clinical Investigations in Colorado 2019 . FDLI. 2019; 18-25.
National Institute of Drug Abuse (NIDA)
Conducts scientific research with cannabis and cannabis compounds Oversees the cultivation of cannabis at the University of Mississippi
Holds the only license for cultivation since 1968 Cannabis used for research must be obtained through NIDA’s Drug Supply
Program (DSP) and cannot be sourced locally
Researchers must have a DEA Schedule I controlled substances license There are limited product options since they do not cover the spectrum of
cannabinoid profiles that investigators wish to study
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Heike, Newman. Food and Drug Law Journal Symposium Spotlight: Cannabis Clinical Investigations in Colorado 2019 . FDLI. 2019; 18-25.
Food and Drug Administration (FDA)
Provides scientific input for the scheduling of drugs to the DEA Supports the development of drugs from cannabis
Compounds of interest are THC and CBD
Takes enforcement action against cannabis products when necessary Products that present health risks Illegal claims on labeling
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Throckmorton, Douglas. FDA Regulation of Marijuana: Past Actions, Future Plans. ICSB/ASP Joint Meeting. Presented on: April 12, 2016.
Cannabis and ResearchResearch barriersPharmacists’ roleOngoing research
Barriers to Cannabis Research
Illicit status of cannabis (Federal) Schedule I controlled substances license required Both the investigator and site must be registered
Cannot be stored in a state-licensed pharmacy A designated space must be created for storage of the products
Research on products from Colorado dispensaries are limited to observational studies
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Heike, Newman. Food and Drug Law Journal Symposium Spotlight: Cannabis Clinical Investigations in Colorado 2019 . FDLI. 2019; 18-25.
Barriers to Cannabis Research
One source of cannabis for research through NIDA Limited product options Formulations are limited to bulk cannabis, cannabis cigarettes and 30:1 whole plant extract Pure cannabinoids other than THC and CBD are not available
Lower THC content compared to products from dispensaries Colorado dispensaries have products that contain up to 30% of THC compared to 10% in the
NIDA products
Quality concerns Fresh vs frozen cannabis No universally acceptable amount of mold that can be on a cannabis product
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Heike, Newman. Food and Drug Law Journal Symposium Spotlight: Cannabis Clinical Investigations in Colorado 2019 . FDLI. 2019; 18-25.
Barriers to Cannabis Research
Limited research funds Funds cannot be accepted from the cannabis industry due to the Racketeer
Influenced and Corruption Organization Act (RICO) Funding could be expanded if donations were managed appropriately (special funds
distributor system)
Limited NIH grant funding NIH granted $37 million for cannabis research compared to $300 million for tobacco in 2017
and 2018
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Heike, Newman. Food and Drug Law Journal Symposium Spotlight: Cannabis Clinical Investigations in Colorado 2019 . FDLI. 2019; 18-25.
Pharmacists’ Role 5 states have established roles for pharmacists in dispensing cannabis Arkansas
Each marijuana dispensary must be appointed a pharmacist consultant Connecticut
Only pharmacists can apply for and obtain a marijuana dispensary license Minnesota
Only pharmacists can give final approval for the dispensing of medical marijuana New York
A pharmacist must be on the premises and supervise the activities within a marijuana dispensing facility
Pennsylvania A pharmacist or physician must be onsite at primary marijuana dispensing
facilities when the facility is open to patients
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State Medical Marijuana Legislation and the Pharmacist's Role. NCPA. https://www.ncpanet.org/advocacy/state-advocacy/medical-marijuana. Accessed on: October 15, 2019
Ongoing Research Cannabis versus opioids for chronic pain Vaporized plant-based cannabis (THC & CBD) product vs. oxycodone
CBD in Restless Legs Syndrome (RLS)
CBD in Fragile X Syndrome Topical CBD formulation
CBD in Parkinson’s disease Muscle spasticity treatment
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Acknowledgements40
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Questions?