Initially touted as a healthier alternative to nicotine cigarettes, electronic cigarettes (e-cigs) may be anything but. There was little research before they came on the market, and even now, the amount of published research pales in comparison to their variety and popularity.
There are currently more than 15,000 unique vapor “flavors” for e-cigs on the market, with over 3 million users between the ages of 14 and 18. Former FDA Commissioner Scott Gottlieb once said he believes the e-cigarette companies are creating a new demographic market among the youth, rather than helping adult smokers quit. With flavors such as cotton candy, green apple, bubble gum and make-your-own, Gottlieb may have a point.
And now, new research out of Marshall University adds another piece to the puzzle—researchers there have linked a common green apple vape flavor to reward-related behavior in the brain.
Ph.D. candidate Skylar Cooper, research technician Austin Akers and Professor Brandon Henderson examined the green apple flavorant farnesene to understand any potential neurologic changes it cases, and if/how it affects nicotine addiction.
For the study, published in eNeuro, the researchers used adult mice genetically modified to contain fluorescent nicotinic acetylcholine receptors (nAChRs). They gave the mice nicotine, the green apple flavorant farnesene, or both in one room and a saline solution in a second room. The mice consistently chose the farnesene chamber over the saline chamber. By itself—i.e. without nicotine—farnesene exhibited reward-related behavior by promoting high-sensitivity nAChRs in the ventral tegmental area of the brain, or the VTA, which is characterized by its dopaminergic neurons. When combined with nicotine, as done in many e-cig formulations, farnesene was also found to enhance reward-related behavior.
A critical discovery by Cooper and team is that farnesene produced a reward in both male and female mice. Previous research on farnesol, a different green apple flavorant, showed it only produced an effect on males. However, the Marshall team has shown that is not the case for farnesene. Additionally, female mice exhibited reward-related behavior at all doses of farnesene examined (0.1, 1, and 10 mg/kg) while males exhibited reward at only the 0.1 mg/kg dose. The research team believes this may be due to the fact that females metabolize farnesene faster than males—the same way they do nicotine.
“This is a very significant finding considering that >90% of adolescent electronic nicotine delivery systems (ENDS) users and >70% of adult ENDS users prefer flavored products,” the authors write in their paper.
The scientists observed another key difference between farnesol and farnesene. While farnesol caused significant upregulation of α6-containing nAChRs, farnesene did not upregulate nAChRs. Instead, farnesene altered nAChR stoichiometry by increasing the proportion of high- to low-sensitivity receptors. A greater proportion of high-sensitivity receptors enhances the affinity and potency of a standard nicotine dose, which could heighten reward and drug-seeking behavior.
"Given a consistent rise in adolescent use of these products and the addiction crisis we are facing throughout this country, it is vital to identify a role that these flavors have in nicotine addiction and how this may impact the developing brain," Cooper said.
She plans to further her research on the impact flavorants have on nicotine addiction, specifically focusing on age-dependent experiments.
“The finding of enhanced nicotine reward when flavorants are present, and the fact that flavorants alone may be rewarding, further indicates the importance of studying flavorants for their potential to alter vaping-related behaviors,” the authors conclude. “It is critical we depict that ENDS flavors are not a simple additive to the devices, instead they are an enhancer to the addictive properties of nicotine and a potential threat to zero-nicotine flavored ENDS users.”
Photo: Mice chose the farnesene chamber over the saline chamber. Credit: Lead author Skylar Cooper, Ph.D. candidate, Marshall University