Synthetic Cooling Agent in Oral Nicotine Pouch Products Marketed as "Flavor Ban Approved"

Background: US sales of oral nicotine pouches (ONPs) have rapidly increased, with cool/mint-flavored ONPs the most popular. Restrictions on sales of flavored tobacco products have either been implemented or proposed by several US states and localities. Zyn, the most popular ONP brand, is marketing Zyn-Chill and Zyn-Smooth as Flavor-Ban Approved, probably to evade flavor bans. At present it is unclear whether these ONPs are indeed free of flavor additives that can impart pleasant sensations such as cooling. Methods: Sensory cooling and irritant activities of Flavor-Ban Approved ONPs, Zyn-Chill and Smooth, along with minty varieties (Cool Mint, Peppermint, Spearmint, Menthol), were analyzed by Ca2+ microfluorimetry in HEK293 cells expressing the cold/menthol (TRPM8) or menthol/irritant receptor (TRPA1). Flavor chemical content of these ONPs was analyzed by GC/MS. Results: Zyn-Chill ONP extracts robustly activated TRPM8, with much higher efficacy (39-53%) than the mint-flavored ONPs. In contrast, mint-flavored ONP extracts elicited stronger TRPA1 irritant receptor responses than Zyn-Chill extracts. Chemical analysis demonstrated the presence of WS-3, an odorless synthetic cooling agent, in Zyn-Chill and several other mint-flavored Zyn-ONPs Conclusions: Synthetic cooling agents such as WS-3 found in Flavor-Ban Approved Zyn-Chill can provide a robust cooling sensation with reduced sensory irritancy, thereby increasing product appeal and use. The label Flavor-Ban Approved is misleading and may implicate health benefits. Regulators need to develop effective strategies for the control of odorless sensory additives used by the industry to bypass flavor bans. ### Competing Interest Statement The funding organization had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; nor in the decision to submit the manuscript for publication. The content is solely the responsibility of the authors and does not necessarily represent the views of National institutes of Health (NIH) or the Food and Drug Administration (FDA). Outside of the submitted work, SO reports being a member of the American Society of Clinical Psychopharmacology (ASCP) Alcohol Clinical Trials Initiative, supported by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi Tanabe, Otsuka; consultant/advisory board member, Alkermes, Dicerna, Opiant; medication supplies, Novartis; DSMB member for NIDA Clinical Trials Network, Emmes Corporation; and has been involved in a patent application with Novartis and Yale. The other authors have no disclosures to report.