Category: Science

Science-based Regulation?

Photo: Li Ding
Politics and data in tobacco harm reduction
By Cheryl K. Olson
In the last couple of years, I’ve written several articles for Tobacco Reporter on how the U.S. Food and Drug Administration thinks about science. Trying to get a novel nicotine product authorized by the Center for Tobacco Products (CTP)? Tell a story about why your particular vape, pouch or gum, is appropriate for the protection of public health, illustrated by data.
That’s how the system is supposed to work. FDA staff make decisions based on what the science says about the relative health risks and benefits of a novel nicotine product. The CTP’s website states: “Our ability to enact science-based regulation has the true potential to reduce the death and disease toll from tobacco products.”
But evidence suggests that stronger forces have shoved science out of the driver’s seat. Recently released memos from the CTP’s Office of Science show that subjective factors drove the decision to deny a marketing authorization for a flavored vaping product. JTI’s Logic brand was teed up as the first menthol-flavored electronic nicotine-delivery system (ENDS) likely to complete the premarket tobacco product application review process. After CTP leadership changed last summer, the emphasis shifted from how menthol vapes might help adults quit smoking, to the purported risks that any flavored ENDS product (including menthol) posed to youth. Prominent politicians have openly pressured the CTP to eliminate flavored vaping products.
In 2019, a CTP toxicologist filed a complaint that the organization had changed its review process from a “fully quantitative review to a more qualitative one,” according to a report on the Government Executive website. CTP researchers were found to have been retaliated against for raising concerns and disagreeing with interpretations of science.
Disagreements about research findings ought to be dispassionate and evidence based. But in tobacco harm reduction, debates about “the science” are often mere veneers over deeper disputes. Trying to make sense of divergent perspectives on e-cigarettes, researchers from the University of Toronto and the University of Cambridge recently interviewed 21 experts on tobacco and harm reduction. They concluded, “The majority of meanings attached to tobacco harm reduction were rooted in values, ideology, politics and opinions rather than straightforward disagreements about the scientific evidence.”
Some industry commenters found the Reagan-Udall Foundation’s much-anticipated operational evaluation of the CTP to be a damp firecracker. Their report does correctly note that “some issues before CTP are fundamental policy questions that must be informed by science but are not, themselves, scientific issues. Rather, they are policy issues with profound societal impacts.”
Before we can talk about the science, we need to acknowledge the values-laden differences in meaning that make logical, civil discourse about nicotine products so difficult. It would take a book to cover it all, but here are a few of the stumbling blocks.
The Legacy of “Light”
In 2009, Mitch Zeller (future director of the CTP), Dorothy Hatsukami and colleagues laid out a vision and blueprint to guide tobacco control efforts. It focused on harm reduction, defined as “strategies that would reduce morbidity and mortality … from continued use of tobacco or other nicotine-containing products.” It noted the now-famous continuum of risk—with smoking far more hazardous than noncombustible nicotine sources—and cautiously acknowledged a role for “potential reduced exposure products,” between cigarettes and nicotine-replacement therapies.
But the article also made clear that all novel reduced-harm products are burdened with the legacy of past industry deception: “The major concern held by some public health experts is that these new products may be nothing more than a more scientifically sophisticated version of the ‘light’ cigarette.” As tested by smoking machines, such products appeared lower risk; as used by humans, they were not. In the authors’ view, naive public health officials were duped by industry into promoting light cigarettes to health-conscious smokers.
Fear of repeating the experience of “light” cigarettes, where claimed reduced exposure to toxins did not lead to reduced disease or death, shaped the Tobacco Control Act of 2009. A well-intended effort to prevent future deceptive advertising now blocks another stated goal of Zeller and colleagues: to “educate the public accurately on the precise risks of different [nicotine] products.”

Unclear Definitions
Before moving full-time into harm reduction, I studied the potential effects of violent video game content on youth. I learned how important shared, clear definitions are to research. In that case, the biggest problem was defining “aggression.” To some researchers in the field, arguing or play-fighting were equivalent to attacks with intent to harm. A study about time spent virtually running amok has very different implications if the consequences are teasing versus criminal assault.
Nicotine research has similar problems with definitions, often also involving youth. For example, anti-tobacco organizations, such as the Campaign for Tobacco-Free Kids, have long worried that “kid-friendly flavors” might attract teens to experiment with vaping.
What constitutes a “kid-friendly flavor”? As Clive Bates has pointed out, as of 2017, this label was attached to candy store or ice cream shop ENDS flavors, or silly ones like “Unicorn Puke.” Removing them from the market would still leave many options for adults who smoked. But today, by definition, all ENDS flavors—other than “tobacco,” and including menthol—attract kids. This is a classic case of moving the goalposts to achieve a win. (The use of “kids” to represent adolescents is a separate debate.)
Unquestioned Assumptions
In a recent interview, author Malcolm Gladwell defined bad science as “science committed by people who think they know the answer before they start.”
Assumptions about vaping’s harm to youth have an increasingly tenuous relationship to science. Objections used to be automatically couched, as in this 2020 article, as a concern that these new nicotine users “may become addicted to vaping, which may lead to smoking.”
Has the availability of vaping coincided with a youth smoking increase? Look at the newly released results from Monitoring the Future, an ongoing national study of U.S. youth substance use. Among 12th grade students, who are typically aged 17–18, any reported nicotine use other than vaping showed a “quite dramatic” decrease, from 21 percent in 2017 to 8 percent in 2022. (Vaping and marijuana use have also dropped, and stayed down.)
By contrast, past-year alcohol use by 12th graders is up, at 52 percent. Documented youth appeal of “alcopop” flavors receives little attention. Interestingly, a Google Scholar search for recent papers on “flavored alcohol youth” brings up more articles on e-cigarette flavors than on alcohol products.
Data suggesting that the gateway from vaping to smoking may be imaginary does not make it less real in the minds of believers. The Campaign for Tobacco Free Kids’ website still describes a vaping epidemic and “serious health risks to the health of young people.” Their list of risks consists of the possibility that nicotine “can harm … parts of the brain responsible for attention, memory and learning,” the risk of nicotine addiction and the increased risk of smoking or “future addiction to other drugs.”
On one hand, we see declining nicotine use and limited real-world evidence of specific health harms to youth. On the other, we see hundreds of thousands of dead adult smokers every year. It’s hard to understand how U.S. regulators consistently weight the former more heavily than the latter. The Reagan-Udall report singled out this balance (on page 15) as one that “scientific analysis alone will not resolve.”

A Shared Goal
Finally, we come to the ultimate policy controversy that research can inform but not solve: Is the goal to end all nicotine use (and addiction)? Or, is the goal to reduce tobacco-linked death and disease? Whether the latter goal is your endgame, or just step one of two, all sides ought to be able to work toward it together.
Dismissing data that doesn’t fit a desired narrative has consequences for public health. As eight respected U.K. experts wrote in response to repudiations of tobacco harm reduction: “The pursuit of arguments that vaping cannot help people to quit smoking, in the face of clear evidence that it does, risks undermining public trust in science.”
It’s time to rethink our assumptions and take a fresh look at patterns of evidence. One pattern we observe, exemplified by Karl Fagerstrom’s new country-by-country analysis, is that more use of reduced-risk noncombustible tobacco is linked to less smoking. Let’s start a discussion about how to rapidly put attractive, lower risk nicotine products in the hands of people who smoke.
Cheryl K. Olson is a California-based public health researcher who specializes in behavioral health issues and consults on tobacco product behaviors via McKinney Regulatory Science Advisors. She spent 15 years on the faculty of Harvard Medical School.

January 1, 2023
Dual Users Likely to Keep Smoking: Study

Photo: Teo
Most adults who both smoke and vape are likely to carry on smoking or continue dual use over the long term, according to new research published in Tobacco Control.
Researchers looked at 545 dual users in waves one through five (2013/2014 to 2018/2019) of the U.S. Population Assessment of Tobacco and Health Study.
Over the six years of data, quitting vaping early but continuing to smoke was the most common pattern for almost half of participants (42 percent). Only 10 percent of participants quit both vaping and smoking early, and 15 percent of dual users continued to use both products.
The frequency of vaping and smoking, nicotine dependence, use of cannabis and other tobacco products at wave one were all influential. Dual users who smoked less frequently at wave one were more likely to quit both products early or to gradually quit smoking.
This is an observational study, and product use was based on self-report and not biochemically verified. No information was available for product use between waves.
“Our findings suggest that smoking reduction could help dual users to quit using both products; additionally, for those smokers unable or unwilling to quit using nicotine, cutting down on smoking could help them switch to exclusive [vape] use,” wrote the authors.
Their results also suggest that “before 2019, [vaping] did not contribute to substantial smoking cessation at the population level.”
“Continued monitoring of trajectories and their predictors is warranted considering the rapid evolution of the [vaping] marketplace,” the authors wrote in a press release.
December 14, 2022
New Genes Connected to Tobacco Addiction

Image: Vlad Kochelaevskiy
Over 2,300 genes are associated with alcohol and tobacco use, according to new Penn State research published in Nature.
“We’ve now identified more than 1,900 additional genes that are associated with alcohol and tobacco use behaviors,” said Dajiang Liu, professor and vice chair for research in the Department of Public Health Sciences. “A fifth of the samples used in our analysis were from non-European ancestries, which increases the relevance of these findings to a diverse population.”
About 400 genes were discovered in a previous research study.
“It is promising to see that the same genes are associated with addictive behaviors across ancestries,” said Liu in a statement. “Having more robust and diverse data will help us develop predictive risk factor tools that can be applied to all populations.”
Within two years to three years, according to Liu, using these genetic risk factors would be refined and become routine in care for individuals already identified as having increased risk for alcohol and tobacco use.
“This project leveraged large amounts of data to identify common genetic risk factors across diverse populations,” said Kevin Black, interim dean of the College of Medicine. “Using these findings to develop screening tools for diseases of despair is the kind of innovation that will help our college lead the way in using health informatics to contribute to health preservation and disease treatment in our communities.”
December 8, 2022
‘Evidence on Heating Products Substandard’

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The quality of evidence available about heated-tobacco products (HTPs) is substandard, and policymakers should be wary of claims made about their role in harm reduction, say the authors of a new study published in Tobacco Control.
HTPs have gained popularity in recent years, with proponents insisting they are less harmful to health than conventional cigarettes. However, researchers at the University of Bath argue that the evidence underpinning these claims is largely unrepresentative of real-world use and at high risk of bias.
In their analyses of 40 publicly available clinical trials for HTPs—29 of which were tobacco industry affiliated or funded—the researchers judged most of the available clinical trials “at high risk of bias” given their methodology and choice of study design.
The most common reason for studies being at high risk of bias was performance bias, whereby the interventions allocated were known to participants and those conducting tests. There was also failure to report all results data for all trial measurements, a shortcoming known as selective reporting bias.
The authors argue that presence of these biases compromises the validity of trials and can lead to overestimation of the effects of HTPs. They also identified further limitations within trials, including short durations, restrictive conditions unreflective of real-world circumstances and a lack of relevant comparators, like e-cigarettes.
Bath’s Tobacco Control Research Group says much more detailed, independent research is needed to assess the short-term and long-term health effects of HTPs.
In the meantime, they argue that consumers should be wary of harm reduction claims and that policymakers and regulators should carefully consider the usefulness of these trials when making decisions surrounding HTPs.
“Over recent years, we have seen great expansion in the heated-tobacco market in the U.K. and around the world. This growth has been predicated on a marketing claim that these products are better for health in comparison with traditional cigarettes,” said lead researcher Sophie Braznell from Bath’s Department for Health.
“Our analysis suggests that the picture is far less clear cut. The clinical trials available, which are used by the tobacco industry to substantiate these claims, were often substandard in terms of how studies were conducted and reported, and most were industry-affiliated in some way.
“As more consumers move away from cigarettes toward these new-generation products, we need much better evidence to assess their health impacts now and into the future. In the meantime, the jury is very much still out on their benefits.”
“These findings in relation to clinical trials for heated-tobacco products are significant and we need to be wary of health claims made,” added study co-author Gemma Taylor from the Addiction and Mental Health Group and Department of Psychology at the University of Bath.
“At the same time, though, it is important to note the clear distinction between ‘heated-tobacco products’ and ‘e-cigarettes.’ Consumers and health policymakers must not equate the potential benefits of e-cigarettes in helping people to quit smoking with heated-tobacco products.”
November 10, 2022
‘Reduced Nicotine Decreases Smoking in the Depressed’

Photo: bramgino
Lowering the amount of nicotine in cigarettes to nonaddictive levels may reduce smoking without worsening mental health in smokers with mood or anxiety disorders, according to a study conducted by Penn State College of Medicine and Harvard Medical School researchers. They said reducing nicotine content in cigarettes could also lessen addiction, lower exposure to toxicants and increase a smoker’s chances of quitting.
Recent proposals by the U.S. Food and Drug Administration and the New Zealand government seek to limit the amount of nicotine in cigarettes to minimally addictive levels. Prior research indicates that reducing nicotine content could help smokers quit, but there is little evidence to demonstrate if these policies could adversely affect smokers with current or prior affective disorders like depression and anxiety disorders—which affect an estimated 38 percent of U.S. cigarette smokers.
According to Jonathan Foulds, professor of public health sciences and of psychiatry and behavioral health, smokers with mental health conditions are more likely to have severe nicotine withdrawal symptoms and less success at quitting. He also said there is speculation that lessening nicotine content to very low levels could worsen psychiatric symptoms in smokers with mental health conditions and lead to heavier smoking and increased exposure to toxicants, or harmful chemicals.
The researchers studied 188 smokers with a history of or who had a current mood or anxiety disorder and had no plans to quit. Volunteer participants were randomly assigned to a group that received either research cigarettes containing the usual amount of nicotine (11.6 mg nicotine per cigarette) or a progressively reduced amount of nicotine for an additional 18-week period (the final amount was 0.2 mg nicotine per cigarette). At the beginning and conclusion of the study, the researchers measured levels of cotinine, a metabolite of nicotine, levels of harmful chemicals, cigarette dependence indexes and various mental health measures.

“Our data showed that there wasn’t a significant difference in mental health measures between the groups, suggesting reduced nicotine cigarettes might not have adverse psychological effects on this population.”
Jonathan Foulds, professor of public health sciences and of psychiatry and behavioral health, Penn State Cancer Institute
The researchers observed no statistically significant differences in mental health measures between the two groups at the conclusion of the study. The team used the Kessler Psychological Distress Scale, a six-item self-report assessment where participants reported on a five-point scale the degree to which they experienced feelings or emotions like “nervous,” “hopeless” or “so depressed that nothing could cheer them up.” Scores are developed by summing points for the six experiences. Participants in the reduced-nicotine content group scored an average of 5.3 at the beginning of the study and finished at an average score of 4.6 while participants in the usual nicotine content group scored 6.1 at the beginning of the study and finished around 4.9.
“These findings are important because we want to understand the effect these policies would have on smokers with anxiety or depressive disorders,” said Foulds, a Penn State Cancer Institute researcher, in a statement. “Our data showed that there wasn’t a significant difference in mental health measures between the groups, suggesting reduced-nicotine cigarettes might not have adverse psychological effects on this population.”
Similar to what prior studies reported, Foulds and his team found that groups in the reduced-nicotine content group were absorbing lower amounts of nicotine and ingesting lower levels of harmful carcinogens such as the biomarker 4-(methylnitrosamino)-1-(3-pryidyl)-1-butanol, more commonly known as NNAL. That group also smoked fewer cigarettes and reported lower levels of nicotine addiction by the end of the randomized phase of the trial.
Unique to this study, participants in both groups were also given the choice to “choose their treatment” after the 18-week period. They could go back to using their own cigarettes, continue smoking the research cigarettes or attempt to quit. Of the 188 participants in the study, those randomized to reduced-nicotine content cigarettes were more likely to have quit smoking 12 weeks later (18.1 percent) compared to those in the control (usual nicotine content) group (4.3 percent).
“We believe this is the first randomized trial to find that smokers who used very low-nicotine cigarettes were significantly more likely to have quit smoking (with biochemical verification) three months after the end of the trial,” Foulds said.
“Our results suggest that these policies will likely result in reduced nicotine absorption from cigarettes without worsening the mental health of smokers with mood or anxiety disorders,” said Eden Evins, Cox Family Professor of Psychiatry at Harvard Medical School. “They also suggest that with proper support and resources, smokers with mood and anxiety disorders could quit successfully as a result of these policies.”
November 3, 2022
Nicotine-Degrading Bacteria Identified

Photo: Paulista
Chinese and U.S. scientists have identified a bacteria in the human stomach that can degrade nicotine, reports the Xinhua News Agency, citing a new study published in Nature.
A colony of gut bacteria was found to have reduced intestinal nicotine concentrations in nicotine-exposed mice.
Nicotine is known to activate an intestinal molecule called AMPKα. These molecules contribute to the progression of nonalcoholic fatty liver disease (NAFLD), according to the study.
The authors suggest that Bacteroides xylanisolvens can help reduce smoking-exacerbated NAFLD progression.
The study involved researchers from Peking University, Zhejiang University, Fudan University, the First Affiliated Hospital of Wenzhou Medical University and the U.S. National Institutes of Health.
October 24, 2022
BAT Conducts New Study of Velo

Photo: BAT
BAT has conducted a cross-sectional clinical study of Velo, which is designed to provide new insights into the real-world health impact of its modern oral nicotine pouch product compared to smoking. Protocol details explaining the design have been published in the journal JMIR Research Protocols.
The study evaluates exposure to certain toxicants and early indicators associated with smoking-related disease in people who have been exclusively using Velo for over six months and compares them with groups of smokers, former smokers and never-smokers.
The results are currently being analyzed and will be published by the end of the year.
“Modern oral nicotine pouches are an exciting product category, which build upon the extensive scientific evidence available for snus but are designed to offer adult consumers an improved tobacco-free, reduced-risk alternative,” said Sharon Goodall, BAT’s group head of regulatory sciences, in a statement.
“We have already generated data that shows Velo has a toxicant profile better than snus and is comparable to nicotine-replacement therapy. However, we wanted to generate further evidence to demonstrate the important contribution it can make to tobacco harm reduction. I believe the results of this study will provide important new information, and we look forward to sharing them once available.”
October 17, 2022
Qnovia Raises $17 million for Nebulizer

Photo: Qnovia
Qnovia has raised $17 million to continue development of its RespiRx nicotine-replacement product, reports Richmond Business Sense.
RespiRx is a portable, hand-held nebulizer, a powered medical device that delivers medicine as an inhaled mist and is similar to an inhaler. The device is designed to deliver a nicotine hit more quickly than existing therapies, thus enabling users to better manage withdrawals and, therefore, increase the likelihood of smoking cessation.
Qnovia was founded in 2018 in Los Angeles by Mario Danek as Respira Technologies and rebranded in September. In May, the company appointed former Altria executive Brian Quigley as CEO and Danek as chief technology officer.
The company also moved to Richmond, Virginia, in part because that state offers a more business-friendly environment, according to Quigley, whose tobacco career included a six-year stint as CEO of Altria’s U.S. Smokeless Tobacco Co. subsidiary.
In addition, many of the partners the company works with are on the East Coast. Qnovia contracts with a Boston manufacturer to make its device and a firm in Pennsylvania to create the medicine administered through the device.
Qnovia will use the newly raised funds to develop a proof of concept for RespiRx as a nicotine-replacement therapy product and move it through an FDA approval process before the anticipated start of human clinical trials in 2023.
The product is expected to hit the market as a prescription treatment. Qnovia is also interested in exploring how RespiRx can be used for asthma, pain management, vaccines and other uses.
October 5, 2022
Startup Uses Tobacco to Cultivate Meat

Photo: Victor Moussa
An Israeli food technology startup company is using tobacco plants to help it create vegetarian hamburgers, reports The Jerusalem Post.
BioBetter has deployed tobacco plants as natural bioreactors to create the growth factors necessary for the cellular development of cultivated meat.
According to the firm, this development could significantly reduce the cost of cultured meat and help rapidly advance its commercialization. Cultured meat could eventually replace beef cows, which are a major factor in producing greenhouse gases and promoting hazardous global warming.
“World population growth and dwindling natural resources are going to put incredible strain on meat supply and the already fragile environment in the coming decades,” said BioBetter CEO Amit Yaari. “Cultivated meat offers a promising solution to these problems and can ensure a more resilient supply chain with better economic and environmental returns.”
In addition to addressing environmental challenges, the work will also create a new source of income for local tobacco farmers, who have suffered losses as cigarette consumption dwindles.
Boosted by a fresh injection of venture capital, BioBetter plans to scale up production in 2023 and commercialize its tobacco plant-derived, food-grade growth factor portfolio by 2024.
September 12, 2022
BAT Study Confirms Positive Impact From Switching to Glo

Photo: BAT
The full results from a year-long study showed that smokers switching exclusively to Glo, BAT’s flagship tobacco-heating product (THP), achieved significant and sustained improvements in several indicators of potential harm associated with early disease development compared to smokers who continued to smoke. This included lung disease, cancer and cardiovascular disease.
Published in Internal and Emergency Medicine, the results build upon the favorable changes reported at three and six months. The improvements observed were sustained over the 12 months of the study, adding to the weight of evidence that supports Glo as a less risky alternative for adult smokers who would not otherwise quit, according to BAT.
“The results from this study are the most important data we have ever generated about Glo and for the THP category in general,” said David O’Reilly, director of scientific research at BAT, in a statement.
“This real-world study allows us to assess the changes that adult smokers switching exclusively to Glo experience by assessing early indicators of potential harm associated with disease development. It provides much needed new evidence about the size of the change and durability of the effect switching completely to Glo can have and reinforces Glo’s potential as a reduced-risk product.”
September 6, 2022