Identifying Potential Acute Health Hazards from Exposures to (S)-6-Methylnicotine to Inform Product Development

Presented at the 77th Tobacco Science Research Conference, Atlanta, GA, 2024.

Nixodine-S™ is a bulk ingredient containing (S)-6-methylnicotine ((S)-6-MN) diluted in propylene glycol (PG), and vegetable glycerin (VG), at different ratios. Nixodine-S™ is sold exclusively by Bonguard Naturals through business-to-business transactions and can be used in the manufacturing of products intended for use by adult smokers, including in e-liquids, vape products, and oral products.

What is (S)-6-methylnicotine?

• 6-MN has a similar chemical structure to nicotine, and has been shown to act on the nicotinic acetylcholine receptors (nAChR)
  • Comes in different isoforms, which may produce different results.

History of Nicotine Analog Research

• Academic research on nicotine analogs historically focused on potential applications for neurological conditions, and for use as insecticidal agents.
• Tobacco companies researched nicotine analogs in the 1970s and 1980s to gain a greater understanding of the central and peripheral effects of nicotine and as part of product research and development, however, there is limited published data on the toxicity of (S)-6-MN.
• Previous literature suggests that some nicotine analogs can have higher nAChR binding affinity than nicotine, however, the available data on (S)-6-MN is limited.

Regulatory Considerations

Products containing nicotine analogs are not currently regulated by U.S. FDA under the Family Smoking Prevention and Tobacco Control Act (TCA).

Nixodine-S™ Product(s) Evaluation Program

A scientific evaluation program to better understand the relative health hazards of Nixodine-S™ compared to nicotine was developed for Bonguard Naturals. This program includes a series of studies including among others, 1) acute toxicity testing of the neat (S)-6-MN constituent used in Nixodine-S™ relative to nicotine, 2) an evaluation of the potential for Nixodine-S™ bulk ingredients to activate select nAChRs relative to nicotine, and 3) final product testing considerations.

1. Acute toxicity testing of the neat (S)-6-MN constituent used in Nixodine-S™ relative to nicotine.
   • Acute toxicity of (S)-6-MN relative to nicotine was evaluated in male and female rats exposed to (S)-6-MN or nicotine at doses up to 175 µg/kg bw, via intravenous (i.v.) administration. Animals exposed to the neat (S)-6-MN via i.v. showed greater signs of acute toxicity than animals administered equal doses of nicotine. This information, as well as data from published literature was used to inform the levels of (S)-6-MN concentration in Nixodine-S™ such that Nixodine-S™ could be substituted at a 1 to 1 ratio with nicotine (v/v).
2. Evaluation of the potential for Nixodine-S™ bulk ingredients to activate select nAChRs relative to nicotine.
   • The relative activation potential of Nixodine-S™ and Nixodine-S™ Salt bulk ingredients compared to nicotine was evaluated with the nicotinic α4β2, α3β4, and α6/3/β2β3 receptor subtypes at v/v equivalent concentrations, using an agonist Fluorometric Imaging Plate Reader (FLIPR), in vitro assay. The nicotinic α4β2, α3β4, and α6/3/β2β3 nAChR subtypes were chosen because they are involved in nicotine reward, physical withdrawal, and nicotine-stimulated dopamine release, and thus play an important role in nicotine satisfaction and dependence.  In the in vitro receptor activation assay, both Nixodine-S™ and Nixodine-S™ Salt elicited similar nAChR activation compared to nicotine, indicating the level of neat (S)-6-MN constituent in the Nixodine-S™ bulk product ingredients is likely appropriate for its intended use.  Receptor activation is one of several components relevant to understanding potential consumer satisfaction and dependence. 
3. Testing considerations for finished products.
   • In the absence of regulatory requirements and guidance, research programs to evaluate products containing nicotine analogs could be informed by testing guidelines established for tobacco and nicotine-containing products.  This may include nonclinical studies (e.g., analytical chemistry and toxicology), clinical evaluation, and establishment of post-market surveillance programs.

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