Medical Cannabis … Clinical and Legal Considerations

Christine Roussel, PharmD, BCOPDirector of Pharmacy, Doylestown Hospital

Disclosures

• No financial Disclosures Relevant to the Cannabis Industry

• Program Director, Medical Cannabis Education Course, Philadelphia College of Pharmacy, University of the Sciences

Outline

• Endocannabinoid System

• Cannabis Pharmacology and Formulations

• Clinical Considerations and Adverse Effects

• Legal Considerations Photo by C.Roussel

Pharmacist Objectives

1. Describe key features of the endocannabinoid system, pharmacology, and non-cannabinoid components of cannabis.

2. Outline dosage forms, pharmacokinetics, potential adverse effects and adverse effects including use disorder.

3. Discuss medical cannabis risk versus benefits and patient counseling opportunities.

4. Review federal cannabis law and possible conflicts between state and federal law.

Pharmacy Technician Objectives

1. Describe main components of cannabis and their pharmacology.

2. List dosage forms available and how they work differently.

3. Describe adverse effects associated with medical cannabis and identify resources for more information.

4. Review federal regulations and their conflict with state medical and recreational marijuana laws.

Disclaimer

• Cannabis is currently not FDA approved for any condition.

• Cannabis is currently DEA Schedule 1 (Federal) under the Controlled Substance Act of 1970.

• No currently acceptable medical use• High Potential for abuse

• Investigational use only– IND applications must receive triple agency approvals:

National Institute of Drug Abuse (NIDA) / DEA / FDA– Product for Federal Research is Sole Source through NIDA

(Unless Import permission is granted)

Cannabinoids as antioxidants and neuroprotectants

US Government Owns Patent

“Cannabinoids are found to have particular application as neuroprotectants, for example limiting neurological damage following ischemic insults, such as stroke and trauma, or in the treatment of neurodegenerative diseases, such as Alzheimer's disease, Parkinson’s disease and HIV dimension”

7https://patents.google.com/patent/US6630507B1/en - Worth Reading!!!!

U.S. Government Grows Cannabis and Supplies it to Patients

1977 – 1993 Federal Compassionate IND (n=13) Grown by University of Mississippi & NIDA

8Pictures by Irvin Rosenfield, author My Medicine. Used with Permission.

Nerve Communication

https://www.shmoop.com/animal-systems/nervous-system.html

Presynaptic Neuron

Postsynaptic Neuron

1. Neurotransmitters Synthesized and stored in vesicles until ready to release

2. Neurotransmitter Binding to Corresponding Receptor

3. Initiates Downstream Effects

Neuro SignalTransmissionAcross the Synaptic Cleft

Image by C. Roussel

• Glutamate• GABA • Acetylcholine• Norepinephrine• Dopamine• 5-HT3• Cholecystokinin

Presynaptic Neuron

Postsynaptic Neuron

2. Endocannabinoids (Anandamide, 2-AG)Synthesized on demand for immediate release

3. Binding at the CB1 Receptor stabilizes vesicles to decrease neurotransmitter release

Neurotransmitter Signaling

Endocannabinoid Signaling is Retrograde Inhibition

1. Too much activity

Image by C. Roussel

CB1 Receptors

Originally publication: Burns, et al. [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. PNAS June 5, 2007 vol. 104 no. 23. Pg. 9800–9805 © [2007] All rights reserved. Reprinted with permission."Shohami E and Horowitz M (ed). Cannabinoids in Health and Disease. Themed special issue, Journal of Basic and Clinical Physiology and Pharmacology 2016; 27(3).

CB1 – Primarily in Brain• NOT significant in brainstem (RR,HR)

Other Locations• Adipocytes • Endocrine and Exocrine Glands• Liver• Heart, Vascular Smooth Muscle Cells

Cannabinoid Pharmacology in CNS● Parasympathetic ● Anti-Nociceptive ● Neuroprotection● Neuroplasticity

Human brain after injection of radio tracer to show the regional distribution of CB1R

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"Originally publication: Ahmad R,, et al. 2016 Whole-body bio-distribution and radiation dosimetry of the cannabinoid type 2 receptor ligand [11C]-NE40 in healthy subjects. Mol Imaging Biol. 2013 Aug;15(4):384-90© [2013]All rights reserved. Reprinted with permission."

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CB2 Receptors• Signally ↓ release of activators and

sensitizersImmunomodulation:• Monocytes and Macrophages

• B-cells and T-cellsLiver, Spleen, Tonsils

Central & Enteric Nervous SystemEndocrine and Exocrine Glands

Medical Cannabis vs MarijuanaCannabis sativa

• Plant reliably grown and handled

• Good Manufacturing Practices

• Assayed, Labeled and Dated for cannabinoids and terpene content

• Proven absence of typical contaminants:

Pictures from www.Steephill.com/science. All rights reserved. Reproduced with permission

• Mold / Yeast• Pesticides• Heavy Metals• Residual Solvents 14

Cannabis Sativa

Hemp – Fiber TypeTall, thick stalk

Fiber Oil Food / Feed

Drug Type (aka Cannabis , Marijuana )

THC + Cannabinoids Terpenes

Industrial Hemp: stalk and seeds are used for textiles, paper, food, detergents, building materials (excludes flower)THC Content < 0.3 – 1.5%Not Scheduled

Cannabis / Marijuana: medicinal / recreational use of cannabinoidsTHC content – 5 – 15+%DEA Controlled Substance

Same Plant –With Different Chemovars

Seed to Sale Tracking

16Pictures by C. Roussel

CO2 Extraction

Pictures by C. Roussel

“Genetic tools weed out misconceptions of strain reliability in Cannabis sativa”

No consistent genetic differentiation between the widely held perceptions of Sativa and Indica Cannabis types.

Instances were found where samples within strains are not genetically similar.

Schwabe A and McGlaughlin M. Genetic tools weed out misconceptions of strain reliability in 1 Cannabis sativa: Implications for a budding industry. bioRxiv preprint first posted online May. 28, 2018. NOT PEER REVIEWED 18

Cannabis: Entourage Effect

CBDcannabidiol

THCtetrahydro-cannabinol

THC-ATetrahydro-cannabinolic

acid

CBCCannabi-

chromene

CBNCannabinol

CBGcannabigerol

PineneLimonene

Myrcene Linalool

ß-Caryo-phyllene

+THCVTetrahydro-cannabivarin Linalool

CannabinoidsFlavonoidsLipidsTerpenesSterols

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Endocannabinoids (Anandamide, 2-AG)

CB1

Image by C. Roussel

• Partial Agonist of CB1 and CB2• Euphoria• Analgesia (primary Pain relief molecule)• Muscle Relaxant• Anxiolytic (low dose) -> Anxiogenic (higher doses)

TETRAHYDROCANNABINOL (THC)

Image by C. Roussel

TETRAHYDROCANNABINOL (THC)

ADVERSE EFFECTS

Psychoactivity vs Psychotoxicity• Impaired cognition• Difficulty concentrating• Memory Impairment

Dizziness, Weakness Increase risk of fallsTachycardiaVasodilation, HypotensionAddiction (1 in 10 chronic recreational users)Hypothermia

Caution in patients with unstable mental health conditions (especially bipolar disorder and schizophrenia).

Image by C. Roussel

• Enhances natural endocannabinoid activity • inhibits anandamide hydrolysis• Agonist at 5-HT (anti-nausea) and TRPV1

(Pain relief)• Potent Immune Modulator = Strong

Anti-Inflammatory Activity• Anti-seizure• Neuroprotective• Decrease negative effects of THC (anxiety,

memory impairment, psychoactivity)

Cannabidiol (CBD)

Negative Allosteric Modification

Image by C. Roussel

Cannabidiol (CBD)ADVERSE EFFECTSDiarrheaHeadacheSuppress AppetiteStimulating (trouble sleeping) …. …..SomnolenceDrug Interactions

World Health Organization: Cannabidiol Critical Review

TERPENES

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LINALOOLSedative

AnxiolyticAnalgesic

Modulate GABA and Glutamate

MYRCENEAnalgesic

Anti-Inflammatory via PGE-2

Anti-ConvulsantSkeletal Muscle Relaxant

ß CARYOPHYLLENESelect CB2 Agonist

AnalgesicGastric Protective

Anti-Inflammatory via PGE-1

Russo, E. B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br.J.Pharmacol. 163: 1344-1364.

PINENEAnti-Inflammatory

BronchodilatorAcetylcholinesterase

Inhibitor (Aids memory)

THC Inhalation

Bioavailability is Variable due to smoking dynamics (10 – 60%)• Depth of inhalation• Duration of Breath Holding• Temp of Vaporizer

Good For Titration and break through because of rapid effects

Import to Teach:• Patient Proper Technique• To wait 5 -10 minutes between

inhalations during titrationHuestis M. Human Cannabinoid Pharmacokinetics. Chem Biodivers. 2007 August ; 4(8): 1770–1804.MacCullum C and Russo E. Practical considerations in medical cannabis administration and dosing. European Journal of Internal Medicine. 49 (2018) 12-19.

Typical Onset 0 – 10 minDuration 2- 4 hours

Cannabis (THC) Oral Administration

• Onset 30 – 120 min • ↑ Inter/Intra Patient Variable Absorption • Absorption ↑ w/ high fat meal

• Duration 4 – 8 hours • *Up to 24 hours dose dependent• Lower Peak [THC]• ↑ [11-Hydroxy-THC]

– Longer T1/2 – More potent analgesic activity– More lipophilic

Huestis M. Human Cannabinoid Pharmacokinetics. Chem Biodivers. 2007 August ; 4(8): 1770–1804.MacCullum C and Russo E. Practical considerations in medical cannabis administration and dosing. European Journal of Internal Medicine. 49 (2018) 12-19.

After Administration of 2.5 mg Dronabinol

Oral Mucosal Products

Bypasses Liver MetabolismOnset 15 – 60 mins

Inhalation

MacCullum C and Russo E. Practical considerations in medical cannabis administration and dosing. European Journal of Internal Medicine. 49 (2018) 12-19. Dustin Sulak, Heaer.com

• higher doses that exceed therapeutic threshold in most patients

• poor ability to dose

Don’t confuse Recreational and Medical.

• delivers smaller doses • able to measure dose

More Appropriate for Medicinal Use

CBD Routes of AdministrationOral CBD

• bioavailability is between 13% and 19%• significant first-pass metabolism• absorption ↑ w/ high fat meal• sublingual

Aerosolized CBD • rapid peak plasma concentrations in 5–10 minutes • higher bioavailability than oral administration

Rectal or Vaginal Suppositories• Increased bioavailability: higher absorption + less first pass metabolism

TopicalHuestis M. Human Cannabinoid Pharmacokinetics. Chem Biodivers. 2007 August ; 4(8): 1770–1804.WHO 2018 Cannabidiol Critical Review

Considerations in Dosing … Patient Self-Titration

Start Low, Go SlowSub-psychoactive dosingCannabis Sensitization

Higher Doses -> Increased ADRs Possible Decrease in efficacy

Finding Optimal Dose“The Sweet Spot”Minimal Side Effects

Dose

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Rooted in the Concept:Less is Really More!

Want up regulation of Endocannabiniod receptors…. (not down regulation)

Patient Education

Medical Goals of Therapy:

Symptom Management vs. Disease Modification

- Nausea / Vomiting- Appetite- Anxiety / Depression

- Pain- Spasticity- Inflammation- Sleep Disorders

THC: CBD Chemotypes or Ratios

THC-predominant Ex. 50:1, 19:1, 16:1

Balanced = Intermediate Ex. 1:1, 4:1Psychoactivity

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Psychoactivity is Dose Dependent and can be affected by tolerance and setting.CBD-dominant

Ex. CBD Only, 1:>20

Average [THC] in DEA specimens 1995 - 2014

Elsohly MA, et al. Changes in Cannabis Potency over the Last Two Decades (1995-2014) - Analysis of Current Data in the United States. Biol Psychiatry. 2016 April 1; 79(7): 613–619. doi:10.1016/j.biopsych.2016.01.004.

“All things are poisons, for there is nothing without poisonous qualities. It is only the dose which makes a thing poison.” – Paracelsus

ECS and the Gastrointestinal TractECS regulates energy balance & food intake, acting both in brain & GI tract

•Anandamide (AEA) is mediator of hunger in intestines

•Starvation increases AEA levels & CB1 expression

•THC increases food uptake via CB1 activation

Anandamide on CB receptors in adipose tissue stimulates lipogenesis.Increased adiposity, insulin resistance

Inhibit nausea and vomiting

35National Academy of Science, 2017

Handbook of Cannabis and Related Pathologies. Chapter 45 Cannabis, Cannabinoids, and Visceral Pain by R. Abalo, M. Isabel Martin-Fontelles

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ECS in the Gastrointestinal Tract and affects of Cananbinioids

CBD = targets upregulated CB2 receptors• Anti-inflammatory• Control fluid accumulation• ** controls hunger **

Handbook of Cannabis and Related Pathologies. Chapter 45 Cannabis, Cannabinoids, and Visceral Pain by R. Abalo, M. Isabel Martin-Fontelles and National Academy of Science, 2017

THC = Direct activation of CB 1 receptors • Analgesia• ↓ gastric acid secretion • ↓ contractility • ↓ motility• ↓ formation of gastric mucosal lesions through

enhanced intestinal epithelial barrier functions• Stimulates hunger sensation

Cannabis Hyperemesis Syndrome• THC and CBD both have antiemetic properties low doses … but high

doses associated with…..

• Cyclic periods of vomiting and, often, epigastric pain.• Improvement by hot showering or bathing

• Typically remitted within 2–3 days after cessation of cannabis.

• Possible resistant to usual antiemetics• consider haloperidol or lorazepam

• Fluid and electrolyte replacement

Handbook of Cannabis and Related Pathologies Cannabis. Chapter 48 Hyperemesis Syndrome. Bonnet, U.

CANNABIS IN PATIENT CAREENDOCANNABINOIDS IN THE RESPIRATORY SYSTEM

• National Academy of Science. (2017). The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research.• Preedy, V. (2017). Handbook of Cannabis and Related Pathologies (1st ed.). Oxford, UK: Academic Press, Elsevier.

Short-term (Acute) cannabis smokingBronchodilation and consistent • Improve specific airway conductance• ↑ peak flow measurements• ↑ forced expiratory volume (FEV1)• Reverse bronchospasm in

methacholine challenges

Dries mucous membranes of mouth and nasal passages

Smoke may irritate large air passages of lungs, throat, windpipe

Heavy habitual smokers of cannabis alone• Symptoms of chronic bronchitis (cough

and sputum)• Histopathological bronchial mucosa

abnormalities (destruction of ciliated epithelial cells, increase mucus secreting surface epithelial cells)

• Not associated with increased lung cancer

Cardio-pulmonary exchange transfers cannabinoids to blood then brain

Cardiovascular Effects of “Marijuana”

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Hypotension

Pacher, et al. Nature Reviews Cardiology, 2017; Kattoor, Marijuana and Coronary Heart Disease, ACC Expert Analysis Online, 2016.

↑ SYMPATHETIC STIMULATION

SUPINE ↑ SYSTOLIC AND DIASTOLIC BLOOD PRESSURE

↓ Time to ANGINA

ORTHOSTATIC HYPOTENSION

Pacher P, et al. Cardiovascular effects of and synthetic cannabinoids: The good, the bad and the ugly, Nature Reviews Cardiology, Online 2017 SeptKattoor A, et al Marijuana and Coronary Heart Disease. ACC Expert Analysis Online, 2016 Sept 22

4.8-fold higher risk of MI within first hour after Inhaling Product• 124 / 3882 patient cohort

• Patients with history of MI, marijuana use > once a week associated with 3 x ↑ Risk of Death

Increased CVD in cannabis users• 316,397 of > 20 million

Marijuana not associate with increased CVD• 4286 with h/o marijuana use

Bradycardia(chronic)

Increased Risk of Myocardial Infarction with Inhaled Cannabis Population Analysis

SELECT PHYTOCANNABINOIDS

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Cannabinoid Areas of Investigation

CBD-A Cannabidiolic acid Anti-emetic, anti-anxiety

THC-A Tetrahydrocannabinolic acidAnti-inflammatory effects via antagonism of tissue necrosis factor alpha (TNF-α); anti-emetic, anti-convulsant, clinical trial on-going for diabetes

CBN Cannabinol 1/10th the psychoactive potency, sedative, antibacterial, inhibition of keratinocytes in psoriasis

CBC Cannabichromene anti-inflammatory, anti-fungal, anandamide reuptake inhibitor

CBG Cannabigerol DGABA uptake inhibitor, antibacterial, inhibition of keratinocytes in psoriasis

Russo, E. B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br.J.Pharmacol. 163: 1344-1364.

Synthetic Cannabinioids(ie. K2, Spice, Crazy Monkey, Chill Out)

• Developed to study the endocannabinoid system

• Up to 200 times more potent that plant based cannabis products• Extreme Potency = Extreme Toxicities

• Vaporizers, E-cigarettes, plant products sprayed with chemicals to burn

• 2015 – 7,797 toxic exposures reported• 25% of events in children 13 to 18 years old

Neurologic symptoms:• Agitation, coma, seizures, toxic psychosis, hallucinations

Synthetic Cannabinoids Extreme Potency = Extreme Toxicities

Organ Function• Severe nausea / vomiting, acute kidney injury, respiratory

depression, death, Cardiac Symptoms

Bleeding … contamination with Brodifacoum• 2018 – 320 cases of severe bleeding and abnormal coagulation

Cannabis Use Disorder (CUDIT-SF) How often in the past 6 months:

1. Did you find you were unable to stop using cannabis once you had started?

2. Have you devoted a great deal of your time to getting, using or recovering from cannabis?

3. Have you had a problem with memory or conversation after using cannabis?

Never(0) Less than monthly (1) Monthly (2) Weekly (3) Daily (4)CUD present with > 2

44Bonn-Miller M. et al., Cannabis Cannabinoid Res. 2016 Dec 1;1(1):252-261.

Ratio of Average [THC]:[CBD] in DEA specimens

Elsohly MA, et al. Changes in Cannabis Potency over the Last Two Decades (1995-2014) - Analysis of Current Data in the United States. Biol Psychiatry. 2016 April 1; 79(7): 613–619. doi:10.1016/j.biopsych.2016.01.004.

Defining Products

Cannabis Strain Analysis. Steep Hill Labs. All rights Reserved. Reprinted with permission. 46

USP Expert Panel on Cannabis• Botanical Identification• Chemical Analysis & Contaminants• Monograph Development

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THC• Dronabinol• Nabilone

CBD•Cannabidiol

Nabixim

olsUS Approval DEA Schedule

Dronabinol (Marinol) 1985 Solid = III; Liquid = II

Nabilone (Cesamet) 2006 II

Cannabidiol (Epidiolex) 2018 V

Nabiximols (Sativex)(1:1 THC: CBD)

NOT APPROVED I (listed as such in NDA)

Slow Titration Decreases Adverse EffectsThe focus is on maintaining / establishing favorable endocannabinoid toneMost Adverse Effects are early and transientGoal is avoid patients ever feeling uncomfortableSafety profile is improved by going slow and Low

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MacCullum C and Russo E. Practical considerations in medical cannabis administration and dosing. European Journal of Internal Medicine. 49 (2018) 12-19.

Drug Interactions:Cannabis Effects on Other Drugs

Potentiate the Effects of Other CNS Depressants•Alcohol, Opioids, Benzos, Muscle Relaxers

Cardiac Effects•Amphetamines

CYP Interactions 2C19, 2C9, 3A4•Cancer •HIV •Anti-Seizure

Oral Chemotherapy Food and Drug Interactions: A Comprehensive Review of the Literature Segal EM 2013 49

Cannabidiol Drug Interaction Examples

Case Report• Patient INR Stable between 2-3

on warfarin dose of 7.5 mg/day• Initiated CBD 15 mg/kg/day and

INR went to 7

Multiple Pediatric Patient Study• Initiation of cannabidiol led to:• average increase of 60% clobaz• average increase of 500%

clobazam’s active metabolites serum concentration

• Additional studies show interactions with Depakote

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Dronabinol US Package Inert Contains Cautions when use with Warfarin

Grayson, L, et al. An interaction between warfarin and cannabidiol, a case report. Epilepsy & Behavior Case Reports 9 (2018) 10-11.

Geffrey, et al. Drug-Drug Interaction between clobazam and Cannabidiol in Children with Refractory Epilepsy. Epilepsia 2015; 56: 1246-1251

Drug Interactions Effects of other drugs on Cannabis

Increase Effects of Cannabis (2 -3 times higher levels)

Amiodarone ClarithromycinAntifungal Drugs Diltiazem

Fluvastatin Certain HIV Drugs

Nabiximols Summary of Medicinal Product Characteristics, European Medicines Agency 3/15

Decrease Effects of Cannabis (50% less Cannabis Effects)

Carbamazepine St. Johns WortPhenobarbital Phenytoin

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World Health Organization:CANNABIDIOL (CBD) Critical Review Report

• No current evidence of that oral CBD administration in humans results in clinically relevant THC-like subjective or physiological effects, or appreciable plasma concentrations of THC or its metabolites.

• At present no public health problems related to misuse, abuse or dependence, including no concern related to “ driving under the influence”

Dependence & CBD• In a human physical dependence study, administration of cannabidiol 1500

mg/day (750 mg 2x daily) to adults for 28 days did not produce signs or symptoms of withdrawal over 6-week period after drug discontinuation

• Suggests that cannabidiol (CBD) does not produce physical dependence

Epidiolex package insert. Carlsbad, CA: Greenwich Biosciences, Inc. 2018 June)

• However, cannabis dependence & withdrawal symptoms are reported in the literature.

• Thus THC (and/or minor cannabinoids) are driving the neuroadaptation that results in a withdrawal syndrome

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Marijuana dependence occurs when the brain adapts to large amounts of the drug by reducing production of and sensitivity to its own endocannabinoid neurotransmitters.” (Rotter et al,2013; Morgan et al,2013) -NIDA. (2018, June 25). Marijuana. Retrieved from https://www.drugabuse.gov/publications/research-reports/marijuana on 2018, September 18https://www.drugabuse.gov/publications/research-reports/marijuana/references

Patient Case #1• 65 year old male with history of DM, neuropathy, dyslipidemia,

uncontrolled HTN, A fib• Current medications include: Metformin, Gabapentin Rosuvastatin,

Amlodpine/Benzapril, Diltiazem

He asks you: “I plan to start Medical Marijuana, What do you think?

You Reply:• What are your goals in taking it?• Are you aware of possible adverse effects?• Are there any concerning drug interactions?

Patient Case # 2• 15 year old male with ADHD and Autism spectrum disorder• Current medications include: Ritalin

The patients mother asks you: “I hear that Medical Marijuana can help my son, Do you know how I can get it?

You Reply:• What are your goals in giving it to him?• Are you aware of possible adverse effects?• Are there any concerning drug interactions?

THE CANNABIS LEGAL PUZZLE

• Procon.org. (2018). 33 Legal Medical Marijuana States and DC: Laws, Fees, and Possession Limits [Image]. Retrieved from https://medicalmarijuana.procon.org/view.resource.php?resourceID=000881• Wikipedia. Updated as of March 15th, 2019

Bradycardia(chronic)

Legal Puzzle

Heterogeneity of State MMJ Programs

State Allowed Home Grown

Budtenders + State Regulated Production

Regulation = Patie

nt Safety

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Licensed HCP + State Regulated Products

Illegally Obtained

CBD falls within the MMJ program if purchased at dispensaries OR if state specifically allows high CBD, low THC products to be sold

Physicians Cannot Prescribe Medical Marijuana

Physicians may NOT: • Order a patient to consume/obtain or order the dispense of a CS I

Physicians Can:• Discuss treatment options, Pros/Cons (including cannabis products)• Recommend that a patient consider the use of cannabis for symptoms

The court held that what it regarded as physicians' "legitimate need to discuss with and to recommend to their patients all medically acceptable forms of treatment" outweighs the government's "legitimate interest in suppressing and controlling the flow of dangerous drugs and controlled substances within the United States."https://www.justice.gov/osg/brief/walters-v-conant-petition

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Where Does Cannabidiol Fit ?

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Permission not requested from this company that fills my email full of cannabis spam and false information that has not been requested!!

Sign in a window of a vape shop 0.1 miles from a Police Station

DEA – Marijuanan Extract Rule (MER)Cannabidiol considered CS I (Dec 2016)

• New drug code established for marijuana extracts = Schedule 1• An extract containing 1 or more cannabinoids that has been derived

from any plant of the genus Cannabis, other then the separated resin (whether crude or purified) obtained from the plant.

• For practical purposes, all extracts that contain CBD will also contain at least small amounts of other cannabinoids.

• Hemp Industry Association contested this, but was denied by court

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Drug Enforcement Agency, Establishment of a New Drug Code for Marihuana Extract. Final rule.

Federal Register 2016 Dec.14;81(240):90194-6.https://www.deadiversion.usdoj.gov/schedules/marijuana/m_extract_7350.html

Agricultural Improvement Act of 2018 (aka Farm Bill) and HEMP

• Allows for legal cultivation of Hemp for growers registered with the state and the Department of Agriculture.

• Hemp removed from the Controlled Substance Act• Allows interstate commerce of legally grown hemp or hemp products• Does not supersede the Food Drug and Cosmetic Act • Does not prohibit the ability to promulgate Federal regulations and guidelines

that relate to the production of hemp

The term ‘hemp’ means the plant Cannabis sativa L. and any part of that plant, including the seeds thereof and all derivatives, extracts, cannabinoids, isomers, acids, salts, and salts of isomers, whether growing or not, with a delta-tetrahydrocannabinol concentration of not more than 0.3 percent on a dry weight basis.

www.congress.gov/115/bills/hr2/BILLS-115hr2enr.pdf

THE CANNABIS LEGAL PUZZLECANNABIDIOL:FOOD DRUG AND COSMETIC ACT HAS AUTHORITY

Unlawful under the FD&C Act to introduce food containing added CBD or THC into interstate commerce, or to market CBD or THC products as, or in, dietary supplements, regardless of whether the substances are hemp-derived. This is because both CBD and THC are active ingredients in FDA-approved drugs and were the subject of substantial clinical investigations before they were marketed as foods or dietary supplements.

• Drug Enforcement Administration. (2017). Establishment of a New Drug Code for Marihuana Extract. Retrieved from https://www.federalregister.gov/documents/2016/12/14/2016-29941/establishment-of-a-new-drug-code-for-marihuana-extract

• https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm628988.htm

Labelling Accuracy of Cannabidiol containing Products obtained on Internet

• Using +/- 10% for label accuracy of CBD content (n=84)• 43% over label• 26% under label• 31% on label

• 18 / 84 samples (22%) contained detectable THC• THC contamination detected as high as 6.43 mg/mL

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Bonn-Miller MO, Loflin MJE, Thomas BF, Marcu JP, Hyke T, Vandrey R. Labeling Accuracy of Cannabidiol Extracts Sold Online. JAMA 2017;318:1708-1709.

THE LEGAL PUZZLE THE FDA ACTIVITY

• https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm436069.htm• https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm628988.htm

Warning Letters2015• 6 companies ->18 products

2016• 8 companies -> 24 products

2017• 4 companies

2018• 1 company

”introduction of a misbranded drug into interstate commerce is a violation “

“intended for treatment of one or more diseases that are not amenable to self-diagnosis or treatment without the supervision of a licensed practitioner. Therefore, it is impossible to write adequate directions for a layperson to use your products safely for their intended purposes. ”

Store in a local Mall ….Selective Reinforcement ?

Photos taken by C. Roussel while school shopping with her children

Question #1

Which of the following statements about the endocannabinoid system is true?

A. Endocannabinoids are synthesized from amino acids.B. Endocannabinoid receptors are the most concentrated g-protein coupled

receptor in the brain.C. Endogenous endocannabinoids have relatively long half lives.

Answer: B

Question #2

Which of the following statements about the pharmacokinetics of cannabis is false?

A. Sublingual cannabis has an onset of action of about 15 min-60 mins.B. Orally ingested cannabis has a predictable onset of action in 5 - 60

minutes.C. Cannabis has a duration of action of 4 - 6 hours.

Answer: B

Question #3Which statement is TRUE about Cannabidiol products?

A. Cannabidiol is associated with dependency.B. Cannabidiol is reliably extracted from hemp seeds, stalks and leaves.C. Over-The-Counter Cannabidiol Products are regulated by the FDA.D. The study by Bon-Miller et al from JAMA showed that Cannabidiol

products purchased on the internet showed consistent compliance with labelling and did not have any contamination with THC.

E. The DEA considers Cannabidiol a “Marijuana Extract” and today it is considered Federally Illegal, while the Cannabidiol product by Greenwich Pharma (brand name Epidiolex) awaits scheduling.

Answer: E

Question #4

The following statements about THC are TRUE?

A. THC can cause impairment and increase a patients risks of falls.B. THC is a molecule that can provide symptom relief for pain, nausea and

sleep disturbances, but at higher doses it can cause anxiety and is not recommended in patients with uncontrolled psychiatric issues.

C. THC is associated with dependency.D. All of the above are true Statements about THC.

Answer: D

References

• Information for Health Care Professionals Cannabis (marihuana, marijuana) and the cannabinoids Prepared by Health Canada. February 2013

• Corroon J, Knight R. Regulatory Status of Cannabidiol in the United States: A Perspective. Cannabis Cannabinoid Res. 2018 Sep 27;3(1):190-194

• Mead A. The legal status of cannabis (marijuana) and cannabidiol(CBD) under U.S. law. Epilepsy Behav. 2017 May;70(Pt B):288-291.

• Russo, E. B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br.J.Pharmacol. 163: 1344-1364.

• Pertwee RG. Handbook of Cannabis. New York, NY: Oxford University Press; 10016.

CE Evaluation Code: 19024