1. Moving Sustainable Medicines Forward™
Product Diversity in the
Medical Cannabis Arena
Jeffrey C. Raber, Ph.D.
© 2017 The Werc Shop, LLC

2. Chemicals of Medical Cannabis
1269 known chemical compounds in/on Cannabis
Cannabinoids (144 known in Cannabis)
THC, CBD, CBN, CBG, CBC, THCV, etc.
THCA, CBDA, CBGA, CBCA, etc.
Diverse array of therapeutic effects
Terpenes & Terpenoids (150 known in Cannabis)
Limonene, Linolool, Pinene, Myrcene, b-Carophyllene
Smell attributes and diverse therapeutic effects
Flavonoids (50 known in Cannabis)
Apigenin, Cannflavin-A, Kaempferol, Vitexin, Orientin
Very strong anti-oxidants – diverse therapeutic effects

3. Most Common in Compositions
Cannabinoids
THCA, THC, CBDA, CBD, CBGA, CBG, CBN
Some on plant ratios of 2:1, >20:1, 3:2
Edibles = array of ratios, common 1:1 THC:CBD
Terpenes & Terpenoids
Limonene, Linalool, Pinenes, b-Myrcene, b-Caryophyllene
Diverse effects – modulates cannabinoids
Ensemble Effect – they are all important

4. Broad Based Medical Utility
Numerous potential ailments can be alleviated
Izzo, et. al., Trends in Pharmacological Sciences 10, (Oct 2009)

5. Whole Plant is Superior Medicine
Single chemical entity not very effective
Marinol® (Dronabinol) – only THC
Two chemicals have better effect than just 1
Sativex® - approximately 1:1 THC:CBD
Cannabis Plant has many compositions!
MORE THAN JUST THC and CBD!!
Ensemble Effect hugely important
What is the Cannabis Composition
More than 1+1 = 2 – Synergy Factor
Wildly different from product to product
Marinol® is a trademark of Solvay Pharmaceuticals, Inc. Sativex® is a trademark of GW Pharmaceuticals, Inc.

6. Cannabinoids – A Broad Term
Phytocannabinoids
Cannabis sativa L. Produced
THCA, CBDA, CBGA, CBCA, etc.

7. Cannabinoids – A Broad Term
Processed Cannabinoids
Decarboxylation has occurred
Processing, Storage, Vaporization

8. Plant Production of Cannabinoids

9. Plant Production of Cannabinoids
THESE ARE WHAT THE PLANTS PRODUCE!

10. Decarboxylation With Heat

11. Product Type Diversity
Plant Material
Flower, Trim, Kief
Concentrates
Shatter, Distillate, Rosin
Sublinguals
Tinctures, Tablets/Mints
Oral Products
Drinks, Chocolate, Brownies, Cookies

12. How Is The Product Made Plant Material Infused Products
Cultivation Conditions
Drying, Curing, Trimming, Packaging
Infused Products
Direct plant material infusion
From concentrate form
Does the product get heated
Impact of terpenes on these methods

13. Different Consumption Methods
Inhalation
Combustion or Vaporization
Sublingual
No first pass metabolism
Topical
What else is present
Oral Products
Matrix effects, absorption rates

14. Concentrate Process is Key
How is the concentrate created
Plant material quality
How many process steps are used
Primary Methods
Water, Hydrocarbon, Alcohol, CO2
Which components remain in final form?
Secondary refinements
Winterization, Distillation

15. Diverse From Plant to Product
How is the final product created
Often relies heavily on concentrate
Formulation Uniformity
Homogeneity of product formation
Different processes yield different chemicals present in the products
Not only consumption routes, but what molecules are being consumed

16. Plant Types are Diverse Too
Consumption Method Diversity
Processing Diversity
Product Type Diversity
All Products Start from Plant Material
What defines a strain
Production process handling
Packaging and Storage conditions

17. Understanding Cannabis Complexity
Analyzing terpenes with GC-FID
Unique method of fingerprinting each varietal
Not all strains are the same or offer same effects

18. Terpenes – Complex and Unknown
Linalool: Floral smelling, is believed to provide some anti-cancer effects and is known to cause severe sedation.
Limonene: Has a citrus scent and may possess anti-cancer, anti-bacterial, anti-fungal and anti-depression abilities.
Pinenes: Pine odor, bronchodilator that opens the lungs to more THC absorption. It also increases focus, self-satisfaction, and energy.
b-Caryophyllene: Sweet, woody, clove taste responsible for anti-inflammatory and neuroprotective effects through CB2 receptor activation.
What are the Ensemble Effects??

19. Overview of Data & Analysis
Over 2200 flowers & 300 concentrates
Subsets used to simplify analysis
Average flower THC = 16%
Average flower CBD = 0.7%
Terpenes are the major differentiator
THC is NOT the major determinant
Product forms can be very different

20. Scatter Plot Many Strains According to Morphological Distinction
Lots of overlap – no distinction

21. Names Present >5 Times
Linalool and Limonene
Terpinolene and Nerol

22. Loading Plot for All Strains

23. Scatter Plot of 4 Popular Strains
Some clustering, some variation

24. Concentrates

25. Concentrates Are Different

26. What Profiling Tells Us
Indica/Sativa/Hybrid designation is not medically meaningful – may indicate plant’s morphology, but not physiological impacts on the patient
New chemotype classifications needed
Multivariant data analysis useful with cannabis
Misnaming of strains in CA appears rampant
Terpenes are major differentiators in this CA data set – sample set bias is likely (high THC)
Phenotypes and differing cultivation conditions lead to additional complexities

27. Repeatable Consumption
Inhalation Apparatus
Combustion versus Vaporization
Pre-rolled versus hand-rolled
Temperature of heat source
Hand held vaporizer versus table top
Inhalation Operation
Strength of inhale
Inhalation duration
Edible and topical products should be consistent in production, then use

28. THC Oral Metabolism Swallowed Felt Excreted (not felt) psychoactive
Non-psychoactive

29. Absorptivity Considerations
Rate of entering the blood stream
Inhalation, sublingual, oral
Each edible product can be very different
What else has been eaten with the medicine?
Oral Metabolites
11-OH, about 5 times as potent as THC

30. Pharmacokinetics
How chemicals are absorbed and processed through the body over a period of time – how long the drug is effective.

31. Pharmacokinetics

32. Oral vs. Inhaled THC

33. Inhalation Device Considerations
Different chemicals delivered each way
Long Path vs. Short Path
Chilled, Cold Water, Ice Cubes
Heating Source Temperature
Rolled cigarette delivers about 30-40% efficiency
Patient inhalation strength and duration
Patients should standardize their own delivery devices and delivery methods
We must educate patients on their devices

34. What is Available When? Combustion & Vaporization - HEAT
Neutral cannabinoids form
THC, CBD, CBG, CBC
Trace cannabinoids can be inhaled
THCA, CBDA, CBN, other derivatives
Terpenes
Tinctures, Oral and Topicals
Exactly what is put in the formulations
No changes due to further heating

35. Definition of “Repeatable”
What is a repeatable dose?
Pharmaceutical specification is 3% of label claim
OTC specification is 10% of label claim
Dietary Supplement is 15% of label claim
Tolerance of dose is based on the safety, toxicity and effectiveness
Does a little more or little less matter?
How sensitive is each patient to cannabis?
Toxicity concerns generally low
Goal is Minimum Effective Dose (MED)

36. Repeatable Consumption
Amount of THC/CBD delivered to patient varies for many different reasons!!
Patients First Need to Select a Standardized Delivery Method
May take some trial and experimentation
Delivery method
Oral
Topical
Inhalation

37. Complex Combinations
Finding a Solution is Difficult

38. Cannabis Is Diversity Ingredients and Production Patient Needs
Use Patterns
Lack of Standards
Supply Chain Shifts
Cannabis Based Medicine Cabinet