Toxicity, Chemistry, and Public Health Relevance of Emerging Nicotine Analog Vapes, Pods, and Pouches.

Electronic nicotine delivery system manufacturers, such as Charlie's Holdings Inc., ECBlend, Outlaw, and NicRiver, have recently introduced nicotine analogs, such as 6-methyl nicotine, 6-MN ("Metatine"), and nicotinamide, NA ("Nixamide," "Nixodine," or "Nixotin-free base and salt") in products to circumvent the U.S. FDA's premarket tobacco product application (PMTA) requirements. Marketed as "tobacco-free," "PMTA-exempt," or "FDA-approved," these compounds now appear in oral nicotine pouches and disposable bars/vapes from brands such as Outlaw Dip, Kumi-Six, SBX, Katchmi, and Spree Bar under proprietary labels including "NoNic6," "Metatine," or "NIC-SAFE." These products often mimic the appeal of conventional nicotine delivery systems, with extensive use of fruit, menthol, and candy-inspired flavorings. Independent testing, however, has revealed inconsistencies between labeled and actual concentrations of 6-MN, alongside the presence of undisclosed chemical additives such as "coolants" and numerous other examples. Additionally, emerging toxicological evidence indicates that 6-MN is more potent than nicotine to cause oxidative, inflammatory, and toxic responses. This includes the activation of NF-κΒ, causes epithelial permeability, and lung remodeling due to extracellular matrix (ECM) modifications. Misleading claims by industry sources include erroneous statements that imply nicotinamide interacts with nicotinic acetylcholine receptors (e.g., methylated nicotine analogs-interaction with α4β2 nicotinic acetylcholine receptors -nAChR interactions). Despite health risks, regulatory frameworks remain ambiguous, enabling companies to circumvent oversight by exploiting loopholes around synthetic analogs. There is a need for rigorous chemical and toxicological studies to evaluate the health effects of nicotine analogs, such as 6-MN and NA, and their interactions with flavorings. This review summarizes current knowledge of chemistry, pharmacology, toxicity, product landscape, flavoring profiles, and labeling practices of 6-MN- and nicotinamide-containing and nicotinamide products, highlighting the urgent need for regulatory clarity, transparent labeling, and further chemico-toxicological assessment.