The Evolution of State Marijuana, CBD, and Hemp Lawsnascsa.org/Conference2019/presentations... · Cannabis contains over 400 compounds Over 100 cannabinoids have been isolated The

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

4

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.

6

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

7

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

17

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

18

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

21

http://erichengelhardt.net/neuro-facts.html

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).

23

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.

24

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

25

Rules & Regulations of CannabisScheduling of cannabisFederal laws & policy

Federal agencies

27

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

28

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

30

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

31

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

32


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

33

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

35



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

36



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

37


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

38

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

39

Acknowledgements40

41

Questions?

Documents

The Evolution of State Marijuana, CBD, and Hemp Lawsnascsa.org/Conference2019/presentations... · Cannabis contains over 400 compounds Over 100 cannabinoids have been isolated The