Of mice and mint: Animal research uncovers a previously unknown role for menthol in tobacco addiction

Cigarette addiction remains one of the common forms of drug addiction, worldwide; it is associated with remarkably elevated risk for heart disease, stroke and multiple types of cancer, explaining why nearly half a million Americans die each year from complications of smoking. A recent study by Brandon Henderson and his colleagues at the California Institute of Technology (Caltech) have revealed a startling new finding – that one of the most common flavorants added to some cigarettes may actually accelerate tobacco addiction. Dr. Henderson, now an Assistant Professor at Marshall University, answered some questions from Speaking of Research about his most recent discoveries.

 

What is menthol and why is it important to study its effects?

Menthol is the most popular flavor additive in tobacco products and the only non-banned flavor in traditional cigarettes (not e-cigarettes) sold in the US. Over time, reports have indicated that smokers of menthol cigarettes quit smoking at lower rates than those that smoke non-menthol cigarettes. Therefore, we are trying to identify the changes in the brain that occur with menthol that may indicate if menthol increases the addictive potential of nicotine (the primary addictive component in tobacco products). As an aside, menthol cigarettes are heavily used by African American smokers (75 – 90%). As a black scientist, this was another reason why I was attracted to studying menthol.

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Menthol is a naturally occurring chemical found in a number of plants, including mints

 

Can you give us a thumbnail sketch of your study and your findings?

Our goal was to examine well-known effects of nicotine on the brain and determine if they are enhanced by menthol. Two of the ‘well-known’ effects of nicotine are an increase in the number of nicotinic receptors (the proteins that bind nicotine) and an increase in the activity of neurons that release the neurotransmitter dopamine. These two events typically occur following long-term exposure (7 – 10 days) to nicotine, contributing directly to nicotine addiction.

Neuroscientists have known that nicotine, by itself, alters the brain to release more dopamine and that is one of the reasons why it is addictive. In this study, we focused on dopamine neurons of the ventral tegmental area, a part of the brain stem. The dopamine neurons that originate in this region are part of the mesolimbic dopamine system. This region is well-characterized for its importance in mediating the rewarding effects of drugs.

When we examined the combination of menthol with nicotine, we found that the combination increases the number of nicotinic receptors to a level that is significantly greater than is produced by nicotine alone. We also found that the combination of menthol and nicotine increased the activity of dopamine neurons to a degree that was significantly greater than what we observed with nicotine alone.

Since we observed that menthol promotes the pro-addictive effects of nicotine in the brain, we believe this may provide part of an answer to why smokers of menthol cigarettes have a much harder time quitting.

 

Mice were involved in your studies. In what ways are they similar and/or dissimilar from human smokers?

The mesolimbic dopamine system of mice is very similar to humans. Like humans, mice will self-administer (voluntarily consume) many drugs of abuse, including cocaine, opioids, and nicotine. Given that mice experience drug reward, similar to humans, they make an excellent model for studying addiction. Two experimental methods are commonly used in rodent models: intravenous self-administration and conditioned place preference, both of which reveal the degree to which nicotine is rewarding in the animal.

One hurdle associated with using mice to study drugs of abuse is that their bodies break down many drugs much more rapidly than humans. Therefore, proper dosing becomes a big concern so that our studies are relevant to humans. For nicotine, the guidelines for dosing were established long before I started science so this was a great benefit to my work with mice.

 

What are the medical or societal implications of your results?

Years ago, the FDA issued a request of information regarding menthol to determine if it should be banned similarly to other flavors that were banned following the Family Smoking Prevention and Tobacco Control Act (2009). This, and other scientific reports, will hopefully be examined by the FDA in determining the future regulations of menthol in cigarettes and e-cigarettes.

 

You just started a new lab as an Assistant Professor at Marshall University. Can you tell us about your future plans for your research and career?

I will continue to study menthol for a few more years because there is still much we need to understand. In the tristate area of Kentucky, West Virginia, and Ohio (where I am originally from), there is a large opioid addiction problem. Most opiate addicts (~80%) also are heavy smokers. I intend to begin studying how opioids and tobacco act together in the brain to promote addictive behaviors.

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Dr. Brian Henderson is an Assistant Professor in the Joan C. Edwards School of Medicine within Marshall University in Huntington, West Virginia

Dr. Brandon Henderson can be found on Twitter at @Dr_BHenderson and on the web at https://www.hendersonlab.org/

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