Cool but not harmless: synthetic cooling agents enhance nicotine reinforcement via the mesolimbic dopamine system

For decades, menthol has held a special status in tobacco regulation. Its cooling sensation makes inhaled nicotine smoother and easier to tolerate, and a large literature links menthol to heavier use and greater difficulty quitting. As U.S. jurisdictions have moved to restrict menthol in combustible and electronic nicotine products, however, the market has not gone flavorless. Manufacturers have instead adopted synthetic cooling agents—most prominently WS-3 and WS-23—that share menthol’s agonism at the cold-sensing TRPM8 receptor, reproducing its cooling sensation without the minty taste. These compounds now appear widely in “non-menthol” and “ice” e-cigarette products, in some cases at concentrations higher than menthol itself, yet they remain unregulated for inhalation [ 1 ]. The pressing question is whether synthetic coolants are inert sensory substitutes or whether, like menthol, they increase the abuse liability of nicotine products.