Being a non-smoker, I hadn’t really thought much about mentholated cigarettes; they connoted just one more, albeit Vick’s Vapo-Rub-type flavor slapped on top of an already potent cigarette smoke flavor. However, as I did more research, I found something more ominous: Menthol acts as a bioactive ingredient, easing smoking-related irritation and influencing the addictive properties of nicotine in both in combustible and e-cigarettes. After all, products like Vick’s Vapo-Rub and menthol cough drops are doing something—soothing sore throats and coughing fits—and unlike menthol in cigarettes, they are currently regulated by the FDA. What are these biological effects, and what is the FDA doing about this? The answers are quite a few, and potentially a lot. The FDA notes that mentholated cigarettes may be easier to start smoking, and potentially harder to quit as well. This is a particularly important problem, because cigarette flavorings like menthol are particularly popular among young people, women, and minorities such as African Americans. “Youth smokers are more likely to use menthol cigarettes than any other age group. More than half (54 percent) of youth smokers ages 12-17 use menthol cigarettes,” said FDA commissioner Scott Gottlieb in a November 2018 statement on flavorings in cigarettes. Several studies have investigated how menthol might ease the negative sensations of smoking, paving the way for addiction. At Yale University, researchers orally administered nicotine and/or menthol to mice in a 2016 paper. They found that menthol could reduce the aversiveness of the taste of nicotine. This seemed to be dependent on the presence of a sensor for menthol, called TRPM8, since mice without this receptor weren't soothed by menthol. This result was also repeated in human smokers in a 2016 study, also at Yale. Menthol could make high concentrations of nicotine administered in e-cigarettes less noxious. A separate set of studies looked into how menthol interacts nicotine physiologically; specifically on the main sensor for nicotine, the nicotinic acetylcholine receptor. A 2015 study by led by M. Imad. Damaj from Virginia Commonwealth University used mice to understand how menthol interacts with number and function these sensors. Over time, injections of nicotine and menthol increased nicotine withdrawal symptoms more than injections of nicotine alone; this result was associated with more nicotine sticking around in the body for longer. A group CalTech, in a 2016 paper, found that menthol alone increases the number nicotinic receptors and affects the makeup of those receptors. Menthol also alters the activity of the dopamine neurons and influences how rewarding nicotine ‘feels,’ in mice. In 2017, they went on to support the idea that menthol and nicotine work together to increase the number of nicotinic sensors in midbrain dopamine neurons specifically—these cells are critical in the process of assessing nicotine as rewarding. (Here’s a nice summary of that work in Nature Magazine.) Other researchers have asked if this principle holds true in people, a much more difficult group to study, ethically and practically. The answers from a study in 2018 were not so straightforward. Yale researchers looked at whether or not menthol could affect nicotine withdrawal symptoms. Although they found some seemingly contradictory results, they saw effects of menthol that differed between menthol and non-menthol-preferring smokers; smokers that prefer menthol cigarettes metabolized nicotine more slowly, and had less nicotine withdrawal after nicotine deprivation. Other studies have looked a genetic reason for menthol preference, and how this relates to the mechanisms involved in cigarette use. The most recent and convincing study that I’m aware of regarding a genetic basis for mentholated cigarette preference found a single relevant genetic variant only found in people of African descent (see NIDCD press release). This important because 86 percent of African American smokers use menthol cigarettes, while other populations use much less—less than 30 percent of white smokers use menthol. The study was led by researchers at the National Institute on Deafness and Other Communication Disorders. Scanning all the protein-coding regions of DNA, they didn’t find any genes related to taste (sensations of sweet, sour, bitter), sensing cold (TRP channels), or sensing nicotine. Instead, they found a gene coding for a not-well characterized type of G-protein coupled receptor, MRGPRX4. In mice, the receptor had been associated with sensing irritation in the lungs. In vitro studies suggest that the receptors encoded by the gene respond differently to menthol. Menthol itself decreases the ability for these receptors to be activated by an agonist, and the receptors encoded by this African-specific variant are even less able to be activated. This suggests that at least in a subset of African American population, menthol may further exacerbate cigarette use and addiction. This means that having the gene variant may make the individual more susceptible to the biological actions of menthol on this receptor. FDA commissioner Scott Gottlieb highlights the importance of menthol cigarette smoking in African Americans: “I believe that menthol products disproportionately and adversely affect underserved communities. And as a matter of public health, they exacerbate troubling disparities in health related to race and socioeconomic status that are a major concern of mine.” This statement eludes to an initiative that has been a long time coming. Back in 2009, Barack Obama passed signed the Family Smoking Prevention and Tobacco Control Act into law. (Here’s a nice summary of the history of FDA regulation of menthol in the New England Journal of Medicine.) From this law, most tobacco flavorings in combustible cigarettes were banned—but menthol slipped through for a variety of political reasons. All these pieces of research point to evidence that menthol might actually be the most dangerous tobacco additive, in terms of biological activity and contributions to addiction. Law makers will have to decide if these pieces of evidence are enough to go back and ban this flavor along with the rest of them.
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Here are a couple of my former students, mid- brain lab in 2010. Fun story, both Kayla Brooks (front) and Nick Petersen (background) ended up working in my thesis lab. Nick worked with me directly, wrote an award-winning thesis, and is an author on one of my papers! Here were our goals:
We did our best to accomplish these goals through a few methods. First, we created a lab as a kind of self-guided tour through the sheep brain. Students could follow simple, step-by-step instructions to successfully dissect out what they needed and when. Of course, in practice, there are still the occasional mishap, and this protocol by no means precluded the need for a great instructor. This way, students didn't have to worry about what to do next, they would just have to worry about what we wanted to worry about--the content. Specifically, we directed students to stop and think about what they were doing by infusing a series of questions throughout the lab. These questions required them to think, make hypotheses and/or do a bit of research to figure out the answers. Some questions had straightforward answers (look up the function of this or that), but others were open for interpretation, and some didn't even necessarily have correct answers. Here is an example to highlight what we were trying to accomplish, regarding the cranial nerves: How do you use anatomical information to infer the function of a nerve? Here are a few factors you may or may not find helpful to consider. Does it help to know:
Explain whether or not you can answer these questions about an individual nerve from gross anatomy (looking at and dissecting the brain from the body as you are doing today). What other information would you need? As you can see, rather than just telling students to identify as many nerves as they could, we took the opportunity to ask students to think about structure, location, and think about how that relationship lends itself to function. Like most questions we posed, they were not necessarily tough to answer, nor did they require essays to answer, but they did require a bit of thought. I did a bit of testing to see how students reacted to the new format. The brain lab lasted two weeks, so I used the second week as a rough comparison group. The first week, where we used this refurbished walk through, included the removal of the dura mater, identification of external structures, and cutting the brain in half and looking at the mid-sagittal structures. In the second week, students were instructed to do a blunt hippocampal dissection to uncover the hippocampus and parts of the midbrain, as well as make slices to identify and find structures like those in the basal ganglia. In this second week, we used our previous methods of giving them a standard sheep brain dissection manual and locating structures, without giving them a more specific walk through instructions or thought questions. Although the two weeks were different in many ways and the comparison is by no means definitive, I found it heartening that students found the first week both more enjoyable and more effective than the second week. To take the above data, I got approval from Cornell's Institutional Review Board! I enjoyed making this lab, and have gotten a lot of positive feedback from it. I'd be more than happy to talk anyone who might want to try this out, and again, please let me know if you want me to send you more resources!
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February 2019
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