A new study led by researchers at the Marshall University Joan C. Edwards School of Medicine reveals that flavor additives commonly used in e-cigarettes may increase the likelihood of vaping behavior in adolescents—even in the absence of nicotine.

Published earlier this month in the Journal of Pharmacology and Experimental Therapeutics, the preclinical study found that certain popular flavorings, including vanilla and cherry, can drive reinforcement-related behaviors similar to those associated with nicotine exposure, particularly in adolescents.

Researchers tested the effects of flavored vapor—including combinations with and without nicotine—on male and female adolescent mice. The study employed the e-Vape self-administration (EVSA) assay, a novel behavioral model that allows mice to voluntarily inhale flavored aerosols. Mice exposed to vanillin or benzaldehyde demonstrated significantly more active responses compared to controls, despite the absence of nicotine.

Four flavor-nicotine combinations showed increased reinforcement-related behaviors: nicotine with menthol, cherry or vanilla, as well as vanilla flavor alone. Even in the absence of nicotine, vanilla-flavored vapor alone was sufficient to trigger behavior indicative of reward-seeking, while cherry flavor alone was not.

“These findings are significant because they demonstrate that some electronic nicotine delivery systems (ENDS) flavors can modulate the brain’s dopamine system—specifically in the nucleus accumbens, a key reward center—even without nicotine present,” said lead investigator Brandon J. Henderson, Ph.D., associate professor of biomedical sciences at the Joan C. Edwards School of Medicine.

“This raises important questions about the potential for addiction-like behaviors in adolescents who use flavored vape products marketed as nicotine-free.”

The research further explored how these flavor chemicals interact at the molecular level, showing that green apple and vanilla compounds can affect nicotinic acetylcholine receptor (nAChR) function—proteins known to play a central role in nicotine addiction.

These findings add to a growing body of research showing that flavorings appear to actively alter the brain’s response to nicotine in ways that could increase dependence—especially among youth, Henderson said.

In addition to Henderson, co-authors on the study include Marshall University medical students Dami Adeshina, Gabrielle Hammers, Sean Hill, Sydney McSweeney, Sabrina Swenson, and Sarah Maddox. The co-authors also include Marshall University Ph.D. students Nathan Olszewski and Samuel Tetteh-Quarshie.