A human translation of research on the neurobehavioral reward and reinforcement of flavored electronic nicotine delivery systems (ENDS)

Abstract Of the more than 10 million people in the United States using electronic nicotine delivery systems (ENDS), the vast majority are using e-liquids with non-tobacco flavors. Fruit flavors are by far the most popular among established ENDS users of all ages, with an estimated 70% of youth and adults using fruit-flavored ENDS.

Most flavored e-liquids on the market use a combination of the same flavoring chemicals, which are approved for food consumption, but not inhalation. While it is clear that flavors enhance the appeal of ENDS and contribute to initiation, laboratory and population-based research has not established a clear link between

flavors and ENDS addiction potential, which is important for policy and prevention. Much of this research has been conducted under the premise that flavors can enhance ENDS addiction potential through their appealing taste. However, during inhalation, flavor chemicals in e-liquids move beyond the mouth to the lungs, where

they can enter the blood stream and pass through the blood-brain-barrier due to their low molecular weight and lipophilicity. Rigorous preclinical research by our team demonstrates that some common flavor chemicals can enhance ENDS reward and reinforcement and increase use frequency by directly altering nicotinic

acetylcholine receptor (nAChR) upregulation and stoichiometry. These nAChR alterations enhance dopamine neurotransmission in the ventral tegmental area (VTA), a key brain region in addiction development. These findings challenge our current conceptualization of how flavor can alter the addiction potential of ENDS by

pointing to a clear neurobehavioral mechanism of specific flavor chemicals. To date, these novel and important preclinical findings have not been translated to humans. The proposed two-phase study will conduct a four-arm double-blind randomized controlled trial of a neuro-active (hexyl acetate) vs. neuro-inactive (ethyl acetate)

ENDS green apple flavors with and without nicotine to determine the effects on biobehavioral markers of addiction potential, including VTA flavor reactivity using functional magnetic resonance imaging and validated laboratory tasks measuring the subjective reward value and relative reinforcement of flavored ENDS. The

specific aims of the R61 phase (n=50) are to: 1) Establish the cumulative vs. acute effects of ENDS flavor; and 2) Confirm that VTA flavor-reactivity is associated with ENDS subjective reward and reinforcement. If milestones are met, the R33 phase (n=200) will include a fully-powered trial to: 1) Determine the independent

and interactive effects of flavor and nicotine on markers of addiction potential; 2) Determine if VTA reactivity mediates the effects of ENDS flavor and nicotine on outcomes; and 3) Explore moderators of the flavor effects, including sex and nicotine dependence. This study will be the first human translation of important and rigorous

preclinical research demonstrating a clear neurobehavioral mechanism for flavor’s ability to enhance ENDS addiction potential. The results have the potential to fundamentally shift our understanding of and ability to characterize the public health risks of flavored ENDS.