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Pharmacology Concepts of Cannabis Therapeutics
PresentersNancy Nurge, NP-BC, MSN, RN
Dr. Denise A. Foster, PhD, MSN, RN, CNEAugust 2019
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ACNA Mission
To advance excellence in cannabis nursing practice through advocacy, collaboration, education, research,
and policy development.
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HousekeepingWelcome to our CE Webinar!
○ All attendees are muted○ Q&A session at end - type questions in chat box
○ Moderator will read questions at end of presentation○ Process for obtaining CE Certificate of Completion
○ Evaluation survey will be emailed to you○ Complete Webinar Evaluation survey○ ACNA will send your Certificate of Completion to your email
Agenda
● Introduction of presenters● Pharmacokinetics & pharmacodynamics of phytocannabinoids
○ Presenter: Nancy Nurge● Physiological effects of phytocannabinoids/phytochemicals
○ Presenter: Dr. Denise A. Foster
Learning OutcomesAt the end of this presentation, the attendee will be able to:
1. Describe the pharmacology of phytocannabinoids. 2. Compare physiological effects of phytocannabinoids and
phytochemicals. 3. Explain the Entourage Effect.
Pharmacokinetics of Cannabis
Cannabis Decarboxylation
CBD-A CBD
THC-A THC
+ =
+ =
+ CO2
+ CO2
Cannabis Routes of AdministrationSmoking Vaporizing Oral/Oromucosal
Onset: 5-10 minutesDuration: 2-4 hours
Onset: 5-10 minutesDuration: 2-4 hours
Onset: 60-180 minutes/15-45 minutesDuration: 6-8 hours
Combustion produces toxic byproducts (tar, hydrocarbons, carbon monoxide, ammonia)
Reduced carbon monoxide but not complete elimination of hydrocarbons
Oils, capsules, tinctures popularEdibles more difficult to doseJuicing/teas do not allow for adequate decarboxylation
Chronic use - respiratory symptoms but not cancer or COPD
Decreased adverse pulmonary symptoms
Tinctures & lozenges intermediate onsetEdibles unreliable onset
Pro: Rapid actionCon: Dexterity required, cough, irritation, 35-50% lost to ‘side-stream’ smoke
Pro: Rapid actionCon: Dexterity required, cough, irritation
Pro: Long duration, less odor, convenient, discreteCon: Titration due to delayed onset
Cannabis Routes of AdministrationTopical Rectal Pechoti
Onset & duration: Variable Onset & duration: Variable Onset & duration: ?
Ideal for local symptoms; limited research & evidence
Possibly indicated for specific populations: cancer, GI symptoms, young, elderly
Possibly indicated for specific populations: cancer, GI symptoms, young, elderly
Pro: Less systemic effectsCon: Only local effects
Pro: Less systemic effectsCon: Administration may be uncomfortable
Pro: Avoids first-pass metabolismCon: Minimal research to suggest it’s as effective as other traditional routes of administration
Cannabis Pharmacokinetics
● Physical-chemical properties of cannabinoids● Degree of tissue vascularization● Individual characteristics, e.g. body composition● Health status
Cannabis PharmacokineticsBased on administration route, cannabis constituents, degree of tissue vascularization, individual characteristics, health status
Rapid in vascular tissues; THC = 3.4 L/kg, CBD = 32 L/kg; THC & CBD are lipophilic, accumulate in adipose tissue
Liver = first-pass metabolism; THC metabolized by P450 enzymes; Δ9-THC converts to Δ11-THC
THC elimination slow due to accumulation in adipose tissue, 20-35% eliminated in urine, 65-80% eliminated in feces
Receptor Activity - THC & CBD
Image credit: Jack Rudd, 2018, “CBD vs THC – What are the Main Differences?” Retrieved from https://www.analyticalcannabis.com/articles/cbd-vs-thc-what-are-the-main-differences-297486
Physiological Effects of Phytocannabinoids
Image credits: Ed Rosenthal
Physiological Effects of THC
● Non-selective cannabinoid receptor agonist● Binds to both CB1 (high) & CB2 (low)● Influenced by density & coupling
○ Has both antagonistic & agonist properties
Physiological Effects of THC
System Physiological Effects
Central Nervous ● Anti- & pro-convulsant● Anxiolytic & anxiogenic● Impairment of short-term memory● Suppression of locomotor activity ● Hypothermia● Immobility ● Antinociception
Tetrad of expected effects
Physiological Effects of THC
System Physiological Effects
Cardiovascular ● Hypotension● Tachycardia bradycardia
Respiratory ● Bronchodilator ● Respiratory complications (chronic use)
Physiological Effects of THC
System Physiological Effects
Central Nervous ● Anti-emetic (nabilone)● Appetite stimulant● ꞵ Dopamine reward threshold
Peripheral Nervous ● ꞵ Tumor necrosis factor-α (TNF-α)● Anti-inflammatory
System Physiological Effects
Central Nervous ● Drowsiness● Dizziness● Dry mouth● Anxiety● Euphoria
● Psychosis to depression● Slowed reaction time● Headache● Cognitive impairment● Blurred vision
Cardiovascular ● Tachycardia● Orthostatic hypotension vs. hypertension
Gastrointestinal ● Cannabis hyperemesis syndrome (chronic use)
Side Effects of THC
Physiological Effects of CBD
● Does not bind to CB1; antagonizes THC○ No impairing effects
● Acts as a CB2 inverse agonist● Inhibits anandamide uptake● Potent cytochrome P450 inhibitor
Physiological Effects of CBD
System Physiological Effects
Central Nervous ● Prevent prion accumulation
Immune: GPR18 & GPR55
● Antagonizes non-CB receptors● Prevents cell proliferation & migration
Respiratory ● Blocks lipooxygenase● ꞵ Inflammation caused by mast cells
Physiological Effects of CBDReceptor Activity
Physiological Effects
CB2 Inverse Agonism
● Anti-inflammation● Inhibits immune cell migration● Inhibits microglial cells, macrophages, & neutrophils● ꞵ Production of TNF-α, interferons, interleukins
Physiological Effects of CBDReceptor Activity
Physiological Effects
CB1 Modulating ● Promotes dopamine activity● Serotonin uptake inhibitor● Enhances norepinephrine activity● Protects neurons from glutamate toxicity● Anticonvulsant● Antinociception
5-HT (Serotonin)
● Antagonism● Anxiolytic
Physiological Effects of CBDAction Physiological Effects
Antimicrobial ● Kills bacteria & fungi● Displays powerful activity against
methicillin-resistant Staphylococcus aureus (MRSA)
Antitumor ● Induces apoptosis: myeloblastic leukemia & glioma cells
● Cytotoxic to breast cancer & other cell lines
Side Effects of CBD
https://www.who.int/medicines/access/controlled-substances/CannabidiolCriticalReview.pdf
“CBD is generally well tolerated with a good safety profile. Reported adverse effects may be as a result of drug-drug
interactions between CBD and patients’ existing medications"
CBD Dose Physiological Effects
Standard dose(<20 mg/kg)
● Drowsiness● Dizziness● Dry mouth
● Lightheadedness● Hypotension● Fatigue
High dose (≧20 mg/kg)
● Diarrhea● Vomiting● Fatigue
● Pyrexia● Somnolence● Abnormal liver function results
Side Effects of CBD
Physiological Effects of CBC
System Physiological Effects
Immune ● Anti-inflammation● Antinociception● Antibacterial, antifungal
Central Nervous ● Antidepressant● Hypothermia● Sedation
Cardiovascular ● With THC, potentiates changes in heart rate without hypotension
Physiological Effects of CBG System Physiological Effects
Central Nervous ● Inhibits the uptake of serotonin & norepinephrine● Inhibits GABA uptake ● Antinociception
Dermal ● Exhibits keratinocyte proliferation
Immune ● Cytotoxicity in high dosage on human epitheloid carcinoma & breast cancer
● Antibacterial against gram-positive, mycobacteria, fungi, MRSA
Physiological Effects of CBN
System Physiological Effects
Central Nervous ● Potentiates THC; ꞵ sedation● ꞵ Follicle-stimulating hormone● Enhances production of testosterone● Anticonvulsant● Anti-inflammatory
Immune ● Potent against MRSA● Recruits mesenchymal stem cells promoting
bone formation
Physiological Effects of THCV
Physiology Physiological Effects
Metabolism ● Reduces food intake● Reduced body weight● Reduces fat content● Reduces leptin concentration● ꞵ 24-hour energy expenditure
CB1 Antagonism ● ꞵ GABA release● Anticonvulsant
Terpenoids in Cannabis sativa
● 140+ terpenoids in cannabis● Yield dependent on multiple mechanisms
○ Chemovar, age, plant part, cultivation environment, harvest time, conditions, drying storage
● > 0.05% considered pharmacologically valuable● Do not activate CB1, CB2 receptors● Modulate THC activity
○ Bind to (but do not activate) CB receptors○ Modulating receptor affinity ○ Alter THC pharmacokinetics
Terpenoids in Cannabis sativa
Linalool Myrcene Limonene Pinene Cineole
Physiological Effects of Monoterpenoids
● Inhibit cholesterol synthesis● Promote hepatic enzyme activity to detoxify
carcinogens● Stimulate apoptosis in cells with damaged
DNA● Inhibit protein processes implicated in
malignant deterioration
Physiological Effects of MonoterpenesMonoterpene Physiological Effects
Limonene ● Inhibits immunosuppression● Reduces symptoms of depression● Antimicrobial ● Anticancer
Pinene ● Anti-inflammatory ● Bronchodilation● Inhibits acetylcholinesterase = memory aid● Antimicrobial● Anticancer
Physiological Effects of MonoterpenesMonoterpene Physiological Effects
Myrcene ● Analgesic, anti-inflammatory, antibiotic, anticancer● Inhibits nitrous oxide in chondrocytes; osteoarthritis?● Inhibits P450 enzymes
Linalool ● Sedating● Anxiolytic● Alleviates skin burns
● Anesthetic● Antiglutamatergic● Anticonvulsant
Cineole ● ꞵ Cerebral blood flow● Inhibits acetylcholinesterase
● Anti-inflammatory ● Antibacterial● Antinociception
Physiological Effects of SesquiterpenesSesquiterpene Physiological Effects
ꞵ-caryophyllene ● Activates CB2 receptors● Anti-inflammatory● Antinociception● Anticancer● Antimalarial● Gastric cytoprotective● Reduces colon inflammation● Protects against cisplatin-induced nephrotoxicity
Humulene ● Antitumor● Anti-inflammatory● Antinociception
Physiological Effects of Flavonoids
Image credits: Ed Rosenthal
Physiological Effects of Flavonoids
● 23 flavonoids● Volatile● Lipophilic● Permeate cell membranes ● Inhibit P450 enzymes● Retain pharmacological activity in smoke ● May bind to opioid receptors● Modulate cell signaling
Physiological Effects of Cannflavins
Cannflavin Physiological Effects
A & B ● Unique to cannabis● Inhibit prostaglandin E2= Anti-inflammatory● Inhibit COX & lipooxygenase enzymes
B ● Therapeutic potential against pancreatic cancer (FBL-03G)
Cannflavin A Cannflavin B
Physiological Effects of Flavonoids
Cannaflavin Physiological Effects
Apigenin ● Anxiolytic● Binds to benzodiazepine receptors● Inhibits production of TNF-α● Interacts with estrogen receptors● Inhibits estradiol-induced proliferation of breast cancer
cells
Physiological Effects of Flavonoids
Cannaflavin Physiological Effects
Quercetin ● Antioxidant● Blocks substance NF-𝚱B
○ Prevents expression of oncogenes, inflammation, apoptosis
○ Also may prevent replication of HIV
Entourage Effect
● Inhibition of FAAH● Modulation by entourage compounds
○ 2-lineoyl glycerol (2-LG)○ 2-palmitoyl glycerol (2-PG)○ Oleoethanolamide (OEA)○ Palmitoylethanoldamide (PEA)
Endocannabinoid Entourage Effect
Image credit: Lee, Y., Jo, J., Chung, H. Y., Pothoulakis, C., & Im. E. (2016). Endocannabinoids in the gastrointestinal tract. American Journal of Physiology. Gastrointestinal and Liver Physiology, 311, G655-G666. doi:10.1152/ajpgi.00294.2015
Phytocannabinoid Entourage Effect
● Synergism of all plant compounds● Supported by numerous clinical studies● Supports harm-reduction approach
Image credit: https://curepharmaceutical.com
Entourage Effect
Pamplona, da Silva, & Coan (2018)
Meta-analysis ● N = 670● Compared CBD-predominant cannabis extracts v.
CBD isolate● 71% improved with CBD-predominant extracts
compared to 36% using CBD isolate● Dosages per day
○ CBD isolate 27.1 mg/kg/day○ CBD-predominant extracts 6.1 mg/kg/day
● Adverse effects higher in CBD isolate
Entourage Effect
Entourage Effect - Possible Mechanisms
● Bioavailability of compounds● Interference with cellular transport processes● Activation or deactivation of active compounds
to inactive metabolites● Action of synergistic partners at different points
causing multi-target effects● Inhibition of binding to target proteins
Thank you for attending!
Questions?Please type your question into the chat box!
Our moderator will read questions as time permits.
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NEXT CE WEBINAR: Introduction to Cannabis Nursing - October 29, 2019 @ 6:30PM EST
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