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

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

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

Broad Based Medical Utility Numerous potential ailments can be alleviated Izzo, et. al., Trends in Pharmacological Sciences 10, 515-27 (Oct 2009)

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.

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

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

Plant Production of Cannabinoids

Plant Production of Cannabinoids THESE ARE WHAT THE PLANTS PRODUCE!

Decarboxylation With Heat

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

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

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

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

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

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

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

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??

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

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

Names Present >5 Times Linalool and Limonene Terpinolene and Nerol

Loading Plot for All Strains

Scatter Plot of 4 Popular Strains Some clustering, some variation

Concentrates

Concentrates Are Different

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

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

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

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

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

Pharmacokinetics

Oral vs. Inhaled THC

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

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

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)

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

Complex Combinations Finding a Solution is Difficult

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