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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.
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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
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Can We Use Existing Inhaled Flavor Regulations?
Some Pieces That Can Be Used
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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
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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.
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Why Not Wait and Use Nicotine Flavor Regulations?
Cannabis & Tobacco Are Different
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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
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Is This an Unprecedented Situation?
No, We Have Been Here Before
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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
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Where Do We Start?
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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?
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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]
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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
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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.
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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…”
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How Do We Begin to Assess Safety?
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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
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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
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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)
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Establish an Independent Expert Panel
Recently Announced: FDA Commissioner Gottlieb to Establish Botanical Safety Consortium (2/11/19)
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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
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Public Relations & Education
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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
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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
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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.
[email protected]+1.310.309.7238
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