Standardizing the Entourage Effect

Regulating terpenes & flavor additives for inhalable cannabis products without throwing the baby out with the bathwater

Brad J. Douglass, Ph.D.

CALL TO ACTION1) Evaluate Flavor Additives for Inhalation Safety• Sanction an Independent Expert Panel

2) Cannabis Vape Flavors Need to Be Regulated Differently Than Nicotine/Tobacco

3) Need Prohibited & Permitted Lists of Ingredients• Establishes a Starting Point

Can We Use Existing Inhaled Flavor Regulations?

Some Pieces That Can Be Used

Can We Use Existing Inhaled Flavor Regulations?

• Tobacco – No Flavor Additive Standards

• Famous list of 599 additives

• Nicotine Vape – Just Starting to Evaluate Flavor Safety

• No Permitted Lists – preliminary Prohibited Lists

• Inhaled Drug Products (e.g. pMDIs, DPIs, Nebulizers)

• No flavor additives

• Perfumes & Fragrances

• Some non-binding regulations (IFRA)

• Chemical Exposure (PELs, NIOSH)

• Different exposure regime: acute/chronic, high-dose

Limited Safety Data on Low-Dose

Preliminary Vapor Product Standards in Europe• Tobacco Products Directive (TPD)• Nicotine vapor products only• Ingredient purity standards• Prohibits: vitamins, caffeine/taurine, CMRs

• British Standards Institute (BSI)• Emissions testing: Metals, degradants (e.g. acrolein) • “One practical risk management measure is to use

only artificial flavours and mixtures…”• AFNOR (French Standards Body)• Similar to BSI recommendations• Additional recommendations on diluents, preservatives, etc.

Why Not Wait and Use Nicotine Flavor Regulations?

Cannabis & Tobacco Are Different

Why Not Wait and Use Nicotine Flavor Regulations?

• Ensemble Effects• The polypharmacy of cannabis is promising

• Terpenes Classified as Flavor Additives • Terpenes could be stricken from nicotine products

• Different Hazard Philosophies• Tobacco traditionally seen as a health detriment

• Different Diluents/Carriers & Chemical Milieu• Different degradants when heated

• Different Use Conditions• 10 V nicotine “mod” vs. 3 V cannabis gentle vape

Not All Inhalation/Vape is the Same

Is This an Unprecedented Situation?

No, We Have Been Here Before

Is This an Unprecedented Situation?

• 1958 Food Additives Amendment• Similar situation with food – even less data• FDA began with a survey of all ingredients currently in use• Established food additive & GRAS pathways

• Food Extract Manufacturers Ass’n (FEMA)• Independent expert panel > FEMA GRAS• Meets U.S. GRAS “expert opinion” requirements

• International FRagrance Association (IFRA)• Independent expert panel > IFRA standards• Voluntary but 90% industry-wide compliance

These Are Models To Emulate

Where Do We Start?

Where Do We Start? • Inventory of [Volatile] Compounds in Cannabis• Reported literature data

• Cannabis lab insight

• Inventory > Permitted Additive List • If naturally in cannabis, a safe place to start?

• Similar paradigm for dietary supplements (NDINs)

• FEMA/TPD/IFRA/NIOSH Lists > Prohibited List• Compounds toxic for any route of administration (e.g. CMR)

• Specific inhalation hazards – FEMA “High Priority” List?

• TPD & BSI prohibited short-lists

• Sensitizers to skin & mucous membranes?

Some Terpenes in CannabisAromadendrene [489-39-4]trans-α-Bergamotene [13474-59-4]β-Bisabolene [495-61-4]α-Bisabolol [515-69-5]Borneol [507-70-0]α-Cadinene [11044-40-9]Camphene [79-92-5]3-Carene [13466-78-9]β- Caryophyllene [87-44-5]Caryophyllene oxide [1139-30-6]1,8-Cineol [470-82-6]p-Cymene [99-87-6]ɣ-Elemene [30824-67-0]β-Eudesmol [473-15-4]ɣ-Eudesmol [1209-71-8](E)-β-Farnesene [18794-84-8]β-Fenchol [470-08-06]

α-Guaiene [3691-12-1]Guaiol [489-86-1]α-Humulene [6753-98-6]Ipsdienol [14434-41-4]D-Limonene [5989-27-5]Linalool [78-70-6]Longifolene [475-20-7]β-Myrcene [123-35-3](E)-Ocimene [3779-61-1](Z)-Ocimene [3338-55-4]α-Phellandrene [2243-33-6]Phytol [150-86-7]α-Pinene [80-56-8]β-Pinene [127-91-3]Sabinene [3387-41-5]Selina-3,7(11)-diene [6813-21-4]α-Selinene [473-13-2]

ɣ-Terpinene [99-85-4]α-Terpineol [10482-56-1]Terpinolene [586-62-9]4-Thujanol [546-79-2]α-Thujene [2867-05-2](+)-Valencene [4630-07-3]α-Ylangene [14912-44-8]

Potentially Concerning Inhaled Flavor Additives

IFRA ProhibitedMusk xylene (81-15-2)Allyl heptine carbonate (73157-43-4)

IFRA Restricted?Capsaicin (404-86-4)

Sensitizers?Coumarin (91-64-5)Eugenol (97-53-0)

Alpha-Diketones & RelatedDiacetyl (431-03-8)2,3-Pentanedione (600-14-6)2,3-Hexanedione (3848-24-6)3,4-Hexanedione (4437-51-8)2,3-Heptanedione (96-04-8)Acetoin (513-86-0)Diacetyl trimer (18114-49-3)

RR

O

O

α,β-Unsaturated Carbonyls2-Pentenal (764-39-6) R

O

R

Aliphatic AldehydesAcetaldehyde (75-07-0) R H

O

Aliphatic Carboxylic AcidsPropionic acid (79-09-4) R OH

O

Aliphatic AminesTrimethylamine (75-50-3) R

NR

R

Case Study: Diacetyl Inhalation

What Is It? • Diacetyl = 2,3-Butanedione: an alpha-diketone• Imparts buttery, “custard” flavor notes

H3CCH3

O

O

What Is The Concern? • Can cause bronchiolitis obliterans (BO), a.k.a. “Popcorn Lung”• Observed in popcorn factory workers in early 2000s

What Are Considered Safe Levels?• Short-Term Exposure Limit (STEL): 25 ppb for 15 minutes• 25 ppb » 16 ng / breath > Total (15 min.) » 3.6 µg• Dose- or concentration-dependent effects?

Recently Published: Park HR, et. al. Sci. Rep. 2019 Feb 1;9(1):1400. doi: 10.1038/s41598-018-37913-9.

Case Study: Diacetyl Inhalation

Recently Published: Park HR, et. al. Sci. Rep. 2019 Feb 1;9(1):1400. doi: 10.1038/s41598-018-37913-9.

“…the expression of multiple genes involved in cilia biogenesis was significantly downregulated by diacetyl and 2,3-pentanedione…”

How Do We Begin to Assess Safety?

How Do We Begin to Assess Safety?

• Start With A Targeted Industry Association• Provide resources & guidance• Cannabis or cannabis additives specific

• Establish an Independent Expert Panel• Modify the finely honed FEMA framework• Incorporate specifics to inhalation & cannabis

• Create Resources for Legislators & Regulators• Harm-minimization approach• Data and research forward

Begin With A Targeted Industry Association

Characteristics of Such an Industry Association • Focused on Cannabis and Cannabis Products• Values Scientific Rigor & Transparency• Appreciates Harm Minimization Strategies• Prepared to Assume a Leadership Position• Assists with Compliance – Develop Analytical Standards• Understands the Importance of Education to Good Policy

Establish an Independent Expert PanelObjectives of Similar Safety Paradigms• General recognition of safety by experts • Experts qualified by training and experience• Base determinations of safety on scientific procedures • Must take into account the conditions of intended use• A standard of “reasonable certainty of no harm”• Avoid conflicts of panel members

Recently Announced: FDA Commissioner Gottlieb to Establish Botanical Safety Consortium (2/11/19)

Establish an Independent Expert Panel

Recently Announced: FDA Commissioner Gottlieb to Establish Botanical Safety Consortium (2/11/19)

Create Resources for Legislators & Regulators

Guide Policy on Flavor Additives for Inhalation• Establish Initial Permitted & Prohibited Lists• Explain Criteria for Selection and Assessment • Provide Comparable Regulatory Resources• e.g. 21 CFR 101.22 treats flavor additives this way for food

• Create FAQs to Address Common Questions & Concerns• Connect Interested Stakeholders• Proffer Related Recommendations• e.g. Vape low-voltage to preserve effects & lessen degradants• Webinars and whitepapers about technical issues

Public Relations & Education

Why Industry Needs to Act• Preserve Standardized Ensemble Effect Formulations• If flavors are disallowed, terpenes could be prohibited• Could relegate terpenes to pharmaceutical products only

• Nobody is Minding the Store• FEMA disclaims inhalation uses• Movement to regulate all vapor products alike

• Cannabis-Specific Independent Expert Panel• Make judgements on low-dose, inhalation safety• Complex issue that demands continued vigilance

• Create Resources for Legislators & Regulators• Significant confusion now

CALL TO ACTION1) Evaluate Flavor Additives for Inhalation Safety• Sanction an Independent Expert Panel

2) Cannabis Vape Flavors Need to Be Regulated Differently Than Nicotine/Tobacco

3) Need Prohibited & Permitted Lists of Ingredients• Establishes a Starting Point

Standardizing the Entourage Effect

Regulating terpenes & flavor additives for inhalable cannabis products without throwing the baby out with the bathwater

Brad J. Douglass, Ph.D.

brad@thewercshop.com+1.310.309.7238