Menthol, tobacco products, and the brain.

What is it about?

Efforts in tobacco control and education have reduced the smoking rate substantially, yet the use of mentholated cigarettes stagnates or increases in 18 to 25 year olds in the US. Mentholated cigarettes account for roughly 25% of the cigarette market in the United States, but are used disproportionately by younger people and women. Menthol is currently the only cigarette flavor additive allowed by the FDA, and a long-standing question is whether menthol is merely a flavor additive or may impact addiction, with conflicting clinical evidence. We investigated the possibility that menthol may influence the effects of nicotine on the brain and behavior using a rat model to control many of the confounds typical of human studies, including differences in smoking patterns and co-morbid substance use. We observed that menthol increased nicotine-induced locomotor sensitization, whereby repeated exposure to the same amount of drug was yet accompanied by augmented behavioral response, a phenomenon reflecting underlying neuroadaptations. Strikingly, this menthol effect was dependent on prior stress exposure. Specifically, adolescent rats who had been exposed to prior stress and were given nicotine co-administered with menthol daily exhibited greater locomotor sensitization than either adult rats or adolescent rats with no prior stress who had been exposed to nicotine only. Furthermore, we found that in this regimen menthol actually reached the brain, and that the behavioral impact of the addition of menthol to nicotine was accompanied by alterations in brain functional connectivity patterns of regions known to be implicated in drug reward, the ventral tegmental area and striatum.

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Why is it important?

To our knowledge, this is the first study to examine the effects of menthol on whole-brain functional connectivity. Additionally, this is the first study to provide experimental evidence that effects of menthol may be modulated by environmental stress during adolescence. Our findings support the notion that beyond flavor, tobacco product mentholation may implicate psychoactive effects that impact nicotine addiction and withdrawal, with potential policy implications for all tobacco products.

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