CBD as medicine from ancient wisdom to modern science. psychoactive tetrahydrocannabinol (THC) vs non-psychoactive cannabidiol (CBD). Current use of CBD.

1. CANNABIDIOL (CBD) AS MEDICINE:
FROM
ANCIENT WISDOM
TO
MODERN SCIENCE
By
Kevin KF Ng, MD, PhD
Former Associate Professor of Medicine
Division of Clinical Pharmacology
University of Miami, Miami, FL.,USA
Email: kevinng68@gmail.com
A Slide Presentation for HealthCare Provider Seminar Sept 2020

2. Lecture Outline
▪ What is cannabidiol (CBD)?
▪ Classification of cannabis plant
▪ Composition of cannabis products.
▪ Discovery of Endocannabinoid System.
▪ Functions of CBD.
▪ Deficiency of endocannabinoids.
▪ Clinical studies of CBD.
▪ Use of CBD.
▪ Summary.
https://bluedelaware.com/2018/05/08/hb401-permitting-cannabidiol-prescriptions-in-delaware/

3. Global drug use in 2016
Percentage of respondents who used the following drugs
https://www.statista.com/chart/9566/prevalence-of-drug-use-worldwide-in-2016/

5. What are cannabinoids?
There are > 144 cannabinoids
▪ Cannabinoids are chemicals found in cannabis
plant.
▪ The most notable cannabinoid is the
phytocannabinoid tetrahydrocannabinol, (THC) the
primary psychoactive compound in cannabis.
▪ Cannabidiol (CBD) is another major constituent of
the plant. It is non-psychoactive.
▪ There are at least 144 different cannabinoids
isolated from cannabis, exhibiting varied effects.
psychoactivenon-psychoactive

6. What is cannabis (drug)?
▪ Cannabis refers to a group of three plants with psychoactive
properties, known as Cannabis sativa, Cannabis indica, and
Cannabis ruderalis.
▪ Cannabis, also known as marijuana, is a psychoactive drug
from the Cannabis plant used primarily for medical or
recreational purposes.
▪ The main psychoactive component of cannabis is
tetrahydrocannabinol (THC), which is one of the 483 known
compounds in the plant including cannabidiol (CBD).
▪ Cannabis can be used by smoking, vaporizing, within food, or
as an extract.
https://www.healthline.com/health/what-is-cannabis#Whats-the-definition-of-cannabis?

7. What is marijuana?
▪ Marijuana refers to the dried leaves, flowers,
stems, and seeds from the Cannabis sativa or
Cannabis indica plant.
▪ Marijuana contains over 480 constituents.
▪ The mind-altering chemical is called
tetrahydrocannabinol (THC).
▪ Inhaled THC quickly passes from the lungs into
the bloodstream. The blood carries the
chemical to the brain and other organs
throughout the body.
https://www.drugabuse.gov/publications/drugfacts/marijuana#mjextracts

8. Legal definition of marijuana
▪ “marihuana” means all parts of the plant
Cannabis sativa L.,
▪ The term “marihuana” does not include
hemp which contains < 0.3% of THC.
https://www.law.cornell.edu/uscode/text/21/802

9. What is cannabidiol (CBD)?
▪ Cannabidiol is a bioactive compound derived from the cannabis plant.
▪ There are more than 144 cannabinoids in the cannabis plant.
▪ Two of the most widely studied cannabinoids are:
▪ Tetrahydrocannabinol (THC)
▪ Cannabidiol (CBD)

10. Discovery of cannabinoids in plants led to the discovery
of the endocannabinoid system in human

11. Cannabis, from plant to pill (2018)
Geographical distribution of the four major
domesticated groups of Cannabis sativa ,
with the center of origin and ancestral
genotype illustrated to be in Central Asia.
Significant hybridization, predominantly
during the last century, has given rise to
two additional groups, hemp and marijuana
hybrids (reproduced from ©Government of
Canada)
https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bcp.13618

12. Countries of origin of accessions assigned to the indica and sativa gene pools.
The arrows suggest human dispersal from the presumed origin of Cannabis in Central Asia.
https://www.researchgate.net/figure/Map-showing-the-countries-of-origin-
of-accessions-assigned-to-the-indica-and-sativa-gene_fig5_226862901

13. Milestones in the discovery of the Endocannabinoid System

14. Scientific classification of cannabis plants
https://plants.usda.gov/java/ClassificationServlet?source=display&classid=CASA3

15. Varieties of Cannabis plants
Hemp: THC < 0.3% Marijuana > THC > 0.3%

16. Vernacular names of marijuana
▪ Pot : condensed version of “potiguaya” or “potaguaya,”
which are short for potación de guaya, a wine or brandy
steeped with cannabis buds
▪ Weed: used to described marijuana cigarettes.
▪ Reefer: slang for marijuana
▪ Marijuana:
▪ Originated from Mexican Spanish or
▪ Originated from Chinese ma ren hua (hemp seed flower)

17. Concentration of cannabinoids in Hemp and Marijuana plants

18. Ratio of CBD : THC in cannabis hybrids
Indica SativaHybrid

19. Cannabis derived products

20. Bioactive compounds in Cannabis plant

21. Constituents of CBD oils
derived from flowers, leaves and stalks

22. Constituents of Hemp Seed Oil
https://www.sciencedirect.com/topics/medicine-and-dentistry/hemp-
seed#:~:text=Hemp%20oil%20typically%20contains%2050,3).

23. Scientific studies of THC led to the discovery of CBD and the
Endocannabinoid System
(AEA)

24. Number of articles on cannabinoids in PubMed up to 2019
phytocannabinoids
endocannabinoids

25. What is the endocannabinoid system?
Endocannabinoid system

26. What are cannabinoids (ligands)?

27. What are cannabinoid receptors?

28. Cannabinoids (ligands) and cannabinoid receptors
Cannabinoids CB1 and CB2 Receptors
plasma membrane

29. Enzymes involved in the synthesis and degradation of
cannabinoids
.
• NAT indicates arylamine N-acetyltransferase;
• NAPE-PLD, N-arachidonyl-
phosphatidylethanolamine phospholipase- D;
• FAAH, fatty acid amide hydrolase;
• COX, cyclooxygenase;
• MAGL, monoacylglycerol lipase;
• 2-AG, 2-arachidonoyl glycerol;
• DAGL, diacylglycerol-lipase;
• AA, arachidonic acid.
https://pubmed.ncbi.nlm.nih.gov/24819878/

30. Targets Mediated by Activation or Inhibition of Cannabinoid Receptors.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820295/

31. Locations of Cannabinoid Receptor CB1 and CB2
https://www.comfortleaf.com/the-endocannabinoid-system/

32. Activation of cannabinoid CB1 and CB2 receptors in
presynaptic neuron and negative feedback loop
Glutamate: excitatory effect
GABA: inhibitory effect

33. Activation of CB2 receptors in immune cells
Adapted from https://www.news-medical.net/life-sciences/Crystal-Structure-of-the-Human-Cannabinoid-Receptor-CB2.aspx
Receptors
Cannabinoids

34. Actions of endocannabinoids
on CB1 and CB2 Receptors
https://emedicine.medscape.com/article/1361971-overview#a4

35. General effects of cannabinoids on their receptors
Adapted from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624216/#:~:text=The%20CB2%20receptor%20is%20expressed,cells%20(8%2C%209).
https://pcrnaturals.com/blogs/news/whats-cbd-got-to-do-with-it

36. Function of endocannabinoid system
Balancing body systems: Homeostasis
Balanced BalancedUnbalanced

37. Physiological conditions influenced by
CB1 and CB2 receptors

38. How does CBD work?
▪ CBD is a partial agonist on CB1 and CB2 receptors:
▪ Action of CBD on CB1 receptor inhibits the release of neurotransmitters.
▪ Action of CBD on CB2 receptor inhibits the release of cytokines and chemokines.
https://www.drawittoknowit.com/course/pharmacology/glossary/pharmacology/pharm
acologic-agonists

39. Immuno-modulation and Anti-inflammatory Actions of CBD
▪ Activation of macrophages and T-cells
▪ Inhibition of neutrophil chemotaxis
▪ Inhibition of release of cytokines and chemokines
▪ Inhibition of cyclo-oxygenase, lipoxygenase, and nitric oxide synthase
▪ Inhibition of generation of prostaglandin, leukotrienes and nitric oxide
https://theroc.us/researchlibrary/Cannabidiol%20(CBD)%20and
%20its%20analogs%20a%20review%20of%20their%20effects.pdf

40. Effect of AEA on CB1R and CB2R expression (2010)
Activated T-cells express higher levels of
CB2R than CB1R at two distinct experimental
time points (24 h and 72 h). These
immunoreactive bands were fully erased by
preincubation of anti-CB1 and anti-CB2
antibodies with their specific blocking
peptides, demonstrating antibody specificity
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0008688

41. Anti-inflammatory Properties of Cannabidiol
Activated macrophage
Modified from https://jpet.aspetjournals.org/content/365/3/652
White blood cell

42. CBD blocks two enzymes that play a key role in inflammation
https://www.wainatural.com/science/CBD-science/anti-inflammatory

43. Anti-inflammatory effects of CBD:
Modulation of cytokine release(2018)
https://www.hindawi.com/journals/bmri/2018/1691428/fig2/
anti-inflammatory

44. CB1 and CB2 activation in experimental disease models (2008)
Modified from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219532/

45. Bioavailability and half-life of CBD
▪ Oral CBD: Capsules, Oils, and Edibles
▪ oral CBD has the lowest bioavailability of all delivery forms.
▪ Half-lives from 10 to 17 hours have been reported for high dosages between 750 mg and 1500 mg
▪ Inhaled CBD: Vaping and Smoking
▪ Smoking has a bioavailability of 31% and a single CBD cigarette containing about 19 mg of CBD can produce peak
blood levels within 3 minutes
▪ The half-life of smoked CBD averages 31 hours.
▪ Vaping produces similar blood CBD concentrations and pharmacokinetics to smoking. There is some risk of lung
irritation with vaping, though less than smoking.
▪ Nebulizers produce peak blood levels in about 36 minutes
▪ Sublingual Drops
▪ Peak blood levels for this method, which involves placing liquid drops of CBD under your tongue, have been measured
within about 2 hours
▪ Oral Spray
▪ in one study, an oral spray consisting of a 50-50 combination of THC and CBD, produced peak blood levels of CBD
at 3.6 hours for a 5 mg dose of CBD and 4.5 hours for a 15 mg dose of CBD, i.e., a three times greater dose
reached peak blood levels in only 20% more time.
▪ Nasal spray
▪ Absorption through the thin mucous membranes lining the nasal passages is quite rapid — reaching maximum
concentration in the blood in 10 minutes or less [
https://dailycbd.com/en/cbd-bioavailability/

46. Clinical use of CBD
▪ Antioxidant
▪ Anti-inflammatory
▪ Immuno-modulatory
▪ Anticonvulsant
▪ Anti-psychotic
▪ Anti-emetic
▪ Support sleep
▪ Modulates side effects of THC

47. Symptom reduction (%) by Epidiolex (CBD) in
7 clinical trials (2020)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053164/

48. Effect of CBD (Epidiolex) on severe childhood onset epilepsy:
Monthly seizure frequencies over time
https://www.sciencedirect.com/science/article/pii/S1525505018301914#f0015

49. Effect of cannabidiol (CBD) on anxiety and poor sleep (n=72)
in a clinical population (2019)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326553/

50. Current cannabidiol (CBD) Clinical Trials (2020)
1. Trial of Cannabidiol to Treat Severe Behavior Problems in Children With Autism
2. Burnout and Distress prevention with cannabidiol in Front-line Health Care workers dealing wIth
COVID-19 (BONSAI)
3. Cannabidiol for CoviD-19 patients With Mild to Moderate Symptoms (CANDIDATE)
4. Novel Cognitive Treatment Targets for Epidiolex in Sturge- Weber Syndrome
5. Study to Evaluate the Safety, Tolerability and Efficacy of Cannabidiol (CBD) as a Steroid-sparing
Therapy in Chronic Spontaneous Urticaria (CSU) Patients
6. Epidiolex (CBD) in Patients With Biochemically Recurrent Prostate Cancer
7. Effects of cannabidiol in Patients: Evaluation (ESCAPE)
8. Cannabidiol and Oral Contraceptive Pills: Exploring a Drug-Drug Interaction
9. Effects of Cannabis on Cognition and Endocannabinoid Levels in Bipolar Disorder Patients and
Healthy Volunteers
10. Use of CBD Oil in the Treatment of Posttraumatic Stress Disorder
11. Osteoarthritis of the Knee Pain Study Using a CBD and THC Sublingual Tablet
12. Cannabidiol Use to Reduce Cravings in Individuals With Opioid Use Disorder on Buprenorphine
(CURB)
https://clinicaltrials.gov/ct2/show/NCT04192370?recrs=a

51. Prescription Cannabinoid Medications
1. Epidiolex oral solution (plant derived CBD) approved by FDA for epilepsy
2. Cesamet capsule (nabilone, a synthetic THC) approved by FDA for chemotherapy
induced nausea and vomiting
3. Marinol capsule (dronabinol, a synthetic THC) approved by FDA for chemotherapy
induced nausea and vomiting, anorexia associated with AIDS
4. Sativex an oromucosal spray ( a combination of THC and CBD in a 1:1 ratio)
approved in Canada and three European countries for neuropathic pain,
rheumatoid arthritis and cancer pain. Not available in US yet.
http://accurateclinic.com/accurate-education-fda-approved-prescription-cannabis-based medications

52. Commercial cannabinoid (CBD) products
▪ CBD Tincture
▪ CBD oil
▪ Broad spectrum
▪ Full spectrum
▪ Isolate
▪ CBD Capsule
▪ CBD infused snacks
▪ CBD Cosmetic products

53. Scientific Study Reveals Major Deviation Between Labelled and
Actual CBD Potency in Commercial Products (2020)
https://www.prnewswire.co.uk/news-releases/gemmacert-scientific-study-reveals-major-
deviation-between-labelled-and-actual-cbd-potency-in-commercial-products-848463314.html

54. Summary
▪ Cannabidiol (CBD) and tetrahydrocannabinol (THC) are bioactive chemicals
found in cannabis plants.
▪ Their isolations led to the discovery of the endocannabinoid system in
human.
▪ THC acts on CB1 receptors which are located mainly in the brain and
peripheral nervous system
▪ CBD acts on CB2 receptors which are found predominantly in immune cells.
▪ CBD has been found to have the following activities:
▪ anti-inflammatory
▪ anti-anxiety
▪ anti-seizure
▪ antioxidant
▪ anti-tumor activities
▪ Clinical studies are limited only to severe seizure disorders.

55. ANY QUESTION?
Please contact
Kevin KF Ng, MD, PhD
Email: kevinng68@gmail.com