Tag Archives: vaping

12/19/23

Health Effects of Vaping

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The American Heart Association recently published a scientific statement on the use of e-cigarettes, “Cardiopulmonary Impact of Electronic Cigarettes and Vaping Products.” It describes the latest usage trends, the current scientific evidence about e-cigarettes and identifies current health impacts. It noted that vaping and e-cigarette use has grown exponentially over the past ten years, particularly among youth and young adults. They have been touted as safer alternatives to tobacco cigarettes, and even as potential tobacco-cessation products. However, e-cigarettes in 2019 led to more than 2,800 hospitalizations.

The CDC reported that as of February 18, 2020, a total of 2,807 hospitalized EVALI (e-cigarette or vaping product use-associated lung injury) cases or deaths were reported. Laboratory data showed that vitamin E acetate, an additive in some THC-containing products, was strongly linked to the EVALI outbreak. The CDC and FDA recommended that people not use THC-containing ENDS—electronic nicotine delivery system. After the identification of the primary cause of EVALI, and a significant decline in EVALI cases, the CDC stopped collecting data from states as of February 2020, the beginning of the COVID pandemic.

By 2019 in the U.S., 27.5% of high school students said they used e-cigarettes or ENDS. These products are the most commonly used tobacco products among youth, a growing number of whom reported never smoking combustible cigarettes. Data from the National Youth Tobacco Survey (NYTS) indicated current use in the past 30 days of ENDS increased from 1.5% in 2011 to 20.8% in 2018, an estimated 3.1 million students. Among middle school students, current e-cigarette use increased from .6% in 2011 to 4.9% in 2018, an estimated 570,000 students. See the following figure from “Cardiopulmonary Impact of Electronic Cigarettes and Vaping Products.”

Data from the 2019 NYTS indicated 25.5% of 12th graders reported current e-cigarette use compared to 11% in 2017. Current THC (cannabis) vaping increased in 12th graders from 4.9% in 2017 to 14.0% in 2019, 4.3% to 12.6% with 10th graders, and 1.6% to 3.9% with 8th graders. The prevalence of ENDS use among youth remained stable despite the pandemic. Data from 2020 showed ENDS use declined to 19.6% among high school students and to 4.7% among middle school students. “Whether this is an artifact of the great societal disruptions from the global pandemic or represents a decreased trend remains to be seen.”

Because of the rapid evolution of ENDS, it is important to examine prevalence rates with other vaping products besides e-cigarettes such as e-hookahs (e-waterpipes). E-hookahs are a new category of vaping devices, introduced in 2014 and recently patented by Philip Morris [the tobacco company], that are marketed as healthier alternatives to traditional hookah fruit-flavored tobacco smoking. Findings from the nationally represented PATH study (Population Assessment of Tobacco and Health; 2014–2015) in children 12 to 17 years of age indicated that 7.7% were identified as ever-users of e-hookahs compared with 14.26% who were ever-users of ENDS products.

Studies in the U.S. indicate a rapid increase in ever and current ENDS use among adults since 2010, “with the vast majority of users being current or former cigarette smokers.” Recent analysis of NHIS (National Health Interview Survey) data from 2014 to 2018 showed young adults 18 to 24 years of age are using ENDS at high rates. Current use increased from 5.1% to 7.6%. There were large increases among never-smokers (1.5% to 4.6%) and former smokers (10.4% to 36.5%).

See “Cardiopulmonary Impact of Electronic Cigarettes and Vaping Products” for a detailed discussion of the acute health effects and toxicity of e-cigarettes and vaping products.

Chronic Health Effects and Toxicity of E-Cigarettes and Vaping Products

E-cigarettes were created in China in the early 2000s and introduced to the US market in 2007. The basic mechanism heats or atomizes a liquid solution or e-liquid that generally contains a humectant (a substance used to keep things moist), nicotine and flavoring agents. The e-liquid formulations can contain other drugs beside nicotine, including THC, methamphetamine and methadone. The FDA attempted to stop the importation of these products, recognizing they could be used as drug-delivery devices. But a 2010 court ruling, Smoking Everywhere, Inc. vs US Food and Drug Administration deemed e-cigarettes should be considered tobacco products, and fall under the 2009 Family Smoking Prevention and Tobacco Control Act.

E-cigarettes and vaping were introduced in the US 16 years ago, and only saw widespread adoption in the past ten years. “We do not yet know the long-term health effects of these products.” Tobacco use was not recognized as a major preventable cause of death until many years after cigarette smoking became widespread. An increasing incidence of lung cancer was not noted until 1930. Definite scientific evidence associating cigarette smoking and lung cancer was not reported until the 1950s.

In 1964, the US Surgeon General report on tobacco and health attributed the increase in lung cancer to cigarette smoking. Only then did cigarette smoking per capita begin to decline. With the delayed development of chronic disease from smoking, lung cancer deaths did not begin to fall accordingly until decades after the 1964 report.

See the following figure taken from “Cardiopulmonary Impact of Electronic Cigarettes and Vaping Products.”

In 2018 an evidence-based summary of the health concerns with ENDS found no available evidence that ENDS use was associated with coronary heart disease, stroke, and peripheral artery disease. There was insufficient evidence that ENDS use was associated with long-term effects on heart rate, blood pressure and cardiac function. There was also no available evidence on whether ENDS use causes respiratory diseases in humans. There was only moderate evidence ENDS use is associated with increased asthma problems, and limited evidence of adverse effects of ENDS exposure on the respiratory system.

There have been few studies of the chronic cardiovascular effects of ENDS because they have only been available for the past 16 years! Assuming similar time delays for the appearance of chronic disease from cigarettes and for ENDS, “epidemiological increases in disease prevalence would not be expected to be observed for years.”

Vaping devices have not been shown to be safe for long-term use. The short- and long-term toxicities of inhaling aerosols generated from liquids containing vegetable glycerin, propylene glycol, nicotine, or flavors are unknown. Inhaling aerosols generated from THC- or CBD-containing liquids, which often contain additional chemical components, also have unknown health effects. Thus, elucidating their long-term respiratory, cardiac, and cancer health effects is a public health priority.

E-Cigarette and Vaping Products as Cigarette-Cessation Products

The Cochrane Review found that nicotine e-cigarettes can be effective in helping people stop smoking for at least six months. They were found to be more effective than nicotine replacement therapy and cessation with e-cigarettes without nicotine. And yet, they strongly discouraged those who have never smoked from using e-cigarettes, especially young people. “This is because they are a relatively new product and we don’t yet know the long-term health effects.”

“Cardiopulmonary Impact of Electronic Cigarettes and Vaping Products” said in the Cochrane Review adverse events were higher at 12 weeks to 6 months in ENDS users when compared to no support or behavioral support only. One study compared e-cigarettes with varenicline (Chantix), finding e-cigarettes were less effective than varenicline. Four of 27 e-cigarette users versus 13 of 27 varenicline users stopped smoking. The main study results assessed smoking cessation and not complete product cessation. “This could mean that participants who quit smoking continued ENDS use.”

Another study compared nicotine ENDS plus a nicotine patch (NRT) with NRT alone and NRT plus nicotine-free ENDS. The patch alone has a 2% abstinence rate. The patch and nicotine-free ENDS had a 4% abstinence rate and the nicotine patch and nicotine ENDS had a 7% abstinence rate. “No current ENDS products have FDA approval as a tobacco-cessation aid. There is only low to moderate confidence of improved cessation with nicotine-containing ENDS products compared with NRT or behavioral interventions.”

There are few empirically tested prevention and cessation programs for youth ENDS use. Using novel technology—text messages, social media—that have been used extensively to advertise ENDS products to youth, as wells as educational efforts targeting parents and health educators, and other methods have been shown to promote smoking cessation among youth. But further work is needed to develop and test effective interventions.

Conclusion

ENDS products have undeniably been increasing in popularity, particularly among young adults and teens, in the past decade. The constituents of these products often include nicotine, which is well established to have negative health effects and strong addictive properties. Other ingredients, particularly in flavored products, have known health risks. Because ENDS products are not regulated as classic therapeutic drugs or devices, there are no dedicated long-term safety studies. Critical questions remain unanswered about the short-term and, in particular, long-term health effects of ENDS products. Because the products have only recently gained widespread use, decades of prospective or retrospective data are not yet available to examine the long-term health effects of cigarettes. Early analysis suggests some utility of ENDS as a smoking cessation product; however, any benefit needs to be juxtaposed with a clear understanding of the health risks of the ENDS products themselves and the risks of product availability leading to nonsmokers initiating ENDS use.

12/13/22

Juul and the Fight to Regulate Vaping

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On June 23, 2022, the FDA ordered JUUL Labs Inc. to stop selling and distributing its products in the US. After reviewing the company’s PMTAs (premarket tobacco product applications), the FDA concluded the applications did not have sufficient evidence the Juul products would benefit public health, as claimed. Some of the company’s study findings had insufficient and conflicting data—“including regarding genotoxicity and potentially harmful chemicals” leaking from their e-liquid pods. The FDA Commissioner said, “Today’s action is further progress on the FDA’s commitment to ensuring that all e-cigarette and electronic nicotine delivery system products currently being marketed to consumers meet our public health standards.”

The FDA thought Juul’s application left regulators with questions about the chemical makeup of its vaping formulations, while Juul thought it submitted enough information and data to address all the concerns. The acting director of the FDA’s Center for Tobacco Products said,

As with all manufacturers, JUUL had the opportunity to provide evidence demonstrating that the marketing of their products meets these standards. However, the company did not provide that evidence and instead left us with significant questions. Without the data needed to determine relevant health risks, the FDA is issuing these marketing denial orders.

The next day the U.S. Court of Appeals placed a temporary hold on the ban, saying Juul’s application warranted “additional review.” Then the FDA announced on Twitter it would allow Juul’s vaping products to remain on the market while it reviewed the application for “scientific issues” unique to the Juul application.

The NYT said the decision to conduct an internal review moved the dispute out of the public eye of the appellate court and returned it to the agency’s private administrative process. The ban in June was celebrated by critics who thought the company should be held accountable for luring teenagers to use its flavored products. Others were critical, saying e-cigarettes are less toxic than traditional cigarettes. Juul argued that it had helped two million adult smokers quit traditional cigarettes. The company also said it had been singled out by members of Congress who influenced the agency to make the ruling.

Juul’s court filing said the agency contended “in more than two dozen places” that Juul did not provide enough data on four chemicals. But Juul said it did provide the data—6,000 pages of data. “Had F.D.A. done a more thorough review (like it did for other applicants), it would have seen data showing that those chemicals are not observable in the aerosol that Juul users inhale.”

Theodore Wagener, the director of the Ohio State University Center for Tobacco Research, said the original ban was surprising, given that independent research teams like his own found that Juul devices were far less toxic than traditional cigarettes. He said Juul aerosol has significantly lower-level and fewer toxicants than cigarettes; and lower chemical levels than other e-cigarettes. It seemed thing were beginning to go Juul’s way, and perhaps was a foreshadowing of the FDA decision.

Then on September 6th Juul agreed to pay $438.5 million to settle a two-year investigation by 33 states into the marketing and sales practices they blamed for starting a national flood in teen vaping. The company did not acknowledge any wrongdoing in the settlement, but said it was trying to resolve past issues while it awaited the FDA decision on whether it would be allowed to continue to sell its products. Connecticut’s attorney general said they were under no illusions that it will stop teen vaping. “But we have essentially taken a big chunk out of what was once a market leader.”

Juul said the settlement aligned with its current business practices. “We remain focused on the future as we work to fulfill our mission to transition adult smokers away from cigarettes — the No. 1 cause of preventable death — while combating underage use.” Under pressure for it marketing practices of targeting youth, Juul revised its business practices and target audience to adult smokers in the fall of 2018. See “Not JUULing Around” and “The Armageddon of Juul.”

The agreement does not resolve all of the company’s legal battles. While Juul had previously reached settlements in lawsuits brought by attorneys general from North Carolina, Washington, Louisiana and Arizona, nine similar cases remain. Major lawsuits filed by New York and California are among those still pending. And about 3,600 lawsuits by individuals, school districts and local governments, have been consolidated in an action that is still wending its way through a California court.

A study done in 2018 and published in the journal Pediatrics looked at 4207 students in ninth-through 12-grades in the Pittsburgh Public Schools. The researchers showed an inverse correlation between protective factors, such as parental monitoring and future orientation and youth vaping. “The differential association of protective factors across tobacco products highlights the unique social and relational features of vaping.”

One of the study’s authors, Kar-Hai Chu, has been studying the evolution of e-cigarettes for the past ten years. He said his research team has done several studies on Juul’s presence on social media, finding at least 25% of Juul’s Twitter followers were under 18. He said their estimate was conservative, as the recent settlement noted above found the number could be as high as 50%.

The immediate and obvious concern was that so many adolescents were being exposed to Juul’s advertisements, but as behavioral scientists, we realized the problems didn’t end there. Not only were kids seeing the ads, but they were sharing them with their friends. In the world of Facebook, Twitter, and Instagram, sharing tobacco content was as easy as a single click.

He described how on Instagram they saw many different flavors of Juul products in colorful cartons. “Decades of research have found that colorful tobacco images are more appealing to younger teens; Instagram was just the latest platform for this strategy.” He then noted a post that made them laugh: “Why do people pee in the Juul room?” But there was truth behind the humor. For teachers and school officials that Twitter post defined the battles they were having.

Kids were using Juul devices in schools, in bathrooms (or Juul rooms), and even in classrooms when teachers’ backs were turned. Schools were desperate for solutions. School administrators had watched adolescent cigarette use decline over the past decade, but this was something new. Yes, it was still a tobacco product, but kids didn’t seem to understand the health impacts. These weren’t teens rebelling by using cigarettes, knowing they were harmful; instead, it was athletes, A-students, and others who believed that e-cigarettes were merely flavored vapor with no impact on their health.

But the golden days for Juul have faded. After Juul gave in to public pressure and stopped selling flavors that appealed to young people, it fell to the fourth favorite among students. Puff Bar, with its candy-and fruit-flavored vapes was first. Altria in December of 2018 bought a 35 percent share of Juul (See “Not JUULing Around”). In a recent filing to its investors, Altria said its share was now valued at $450 million.

Whatever the FDA decision is on Juul, the FDA is purposefully moving to regulate all vaping, all ENDS (electronic nicotine delivery systems). But vaping manufacturers won’t give up without a fight. In an attempt to evade FDA regulation, manufacturers of e-cigarette brands popular with kids have begun to use synthetic nicotine in their products.

However, a new federal law went into effect in April of 2022, clarifying the FDA’s authority to regulate tobacco products containing nicotine from any source. After July 13, 2022, “any new non-tobacco nicotine product that has not received premarket authorization from FDA cannot be legally marketed.” When companies are found to be illegally marketing non-tobacco nicotine products, the FDA will first issue warning letters to achieve voluntary compliance. But the agency will pursue enforcement actions such as civil money penalties, injunction, non-tobacco sales orders, or injunction.

08/17/21

The End of ENDS?

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On Wednesday, June 23, 2021 the Subcommittee on Economic and Consumer Policy held its fourth hearing examining youth vaping in the US. Senator Dick Durbin and the acting FDA Commissioner, Janet Woodcock were witnesses. The FDA is in the process of determining whether e-cigarettes will be legally allowed to stay on the market. “All e-cigarette manufacturers were required to submit Premarket Tobacco Product Applications (PMTAs) to FDA by September 9, 2020, in order to legally stay on the market.” Stat News reported that Senator Durbin and other Democrats accused the FDA of inaction on the issue: “Who is the cop on the beat to whom we entrust our children? It’s the Food and Drug Administration.”

The hearing comes as the FDA begins deciding in earnest which e-cigarette manufacturers can stay on the market, as part of a congressionally mandated process. Manufacturers like Juul, Blu, and Njoy were required to submit marketing applications to the FDA in September but are allowed to stay on the market until at least September 2021, while the agency reviews those applications.

In 2018, the Surgeon General issued an advisory where he declared e-cigarette use among youth an epidemic. “We need to protect our young people from all tobacco products, including e-cigarettes.” Despite this advisory, there has been little concrete action as yet. The chair of the subcommittee said the youth vaping epidemic has continued over the past three years. “More than 20% of high schoolers vape, and 5% of middle schoolers vape.” These are the same levels that led the surgeon general to declare a youth vaping epidemic in 2018. To the FDA, he said:

No matter what your decision on Juul’s PMTA, you know that the problem does not end there. To end the youth vaping epidemic, you’ll have to deny the applications for all products with the same characteristics that made Juul so popular with a generation of children.

Federal officials had singled out Juul for fueling the epidemic because of its intentional advertising aimed at youth and the sleek design of its product, which made Juul far and away the most popular e-cigarette among young people. The company defended its products, saying it took steps to prevent youth from using them. Juul stopped distributing some flavorings to retail stores, but only after the FDA announced plans to restrict the sale of flavored e-cigarettes to young people. The Oversight Committee released internal documents from its investigation of Juul that showed the company knew its products were addictive for teens.

Included in the documents was an internal memo from a Juul-focus group in 2018 that asked the teens why the product was so attractive to kids in Middle School and High School. “Several of the young people responded that the product’s high nicotine content kept kids hooked.” Juul says it chose a high nicotine level for its pods, roughly equivalent to a pack of cigarettes, to entice adults to quit combustible cigarettes. The claim seems somewhat disingenuous, as the company began receiving complaints that its products nicotine levels were too high around one year after Juul launched in 2016.

In an October 2018 CDC press release, “Sales of JUUL e-cigarettes skyrocket, posing danger to youth,” the then director of the CDC Robert Redfield said, “The popularity of JUUL among kids threatens our progress in reducing youth e-cigarette use.” During 2016-2017, Juul Labs’ sales increased 641%, from 2.2 million devices sold in 2016 to 16.2 million devices sold in 2017. Truth Initiative, a nonprofit organization seeking to eliminate nicotine addiction, surveyed 12 to 17-year-olds in April of 2018 to assess how so many young people were getting their hands on Juul products. Seventy-four percent said they obtained Juul in a store. Fifty-two percent said they received Juul from a family member or friend. For more information on Juul, see: “JUUL Is Not a Gem,” “The Armageddon of Juul,” and “Juul’s Empty Harm Reduction Rhetoric.”

While vaping is less harmful than smoking, it still is not safe. As of February 18, 2020, the CDC reported there have been 68 deaths from EVALI—e-cigarette or vaping-associated lung injury. There were 2,807 hospitalized cases or deaths from EVALI. Laboratory data showed that vitamin E acetate, an additive in some THC-containing vaping products was strongly linked to the EVALI outbreak. The CDC recommended that people not use THC-containing e-cigarettes or vaping products. “E-cigarette, or vaping, products (nicotine- or THC-containing) should never be used by youths, young adults, or women who are pregnant.”

Michael Blaha, the director of clinical research at the John Hopkins Ciccarone Center for the Prevention of Heart Disease, shared health information about vaping in “5 Vaping Facts You Need to Know.” While vaping is less harmful than smoking, it still isn’t safe. There are many unknowns about vaping, including what chemicals are included in the vapor inhaled by users and how physical health is affected over the long term. Blaha said people need to understand e-cigarettes are potentially hazardous to their health. “Emerging data suggests links to chronic lung disease and asthma, and associations between dual use of e-cigarettes and smoking with cardiovascular disease. You’re exposing yourself to all kinds of chemicals that we don’t yet understand and that are probably not safe.”

Research suggests nicotine is just as addictive as heroin and cocaine. Many e-cigarette users get more nicotine than smokers because they can buy cartridges that have a higher concentration of nicotine. You can also increase the voltage of an e-cigarette to get a greater hit of the substance. E-cigarettes are not approved by the FDA as smoking cessation tool, even though they have been marketed as such. A study found that most people who intended to use e-cigarettes to stop smoking ended up continuing to smoke both.

According to Blaha, there are several reasons e-cigarettes are enticing to youth. Teens believe vaping is less harmful than smoking. They have a lower cost per-use than traditional cigarettes. They often have added flavorings and there is a lack of smoke from their use. “With no smell, e-cigarettes reduce the stigma of smoking.” Blaha said:

What I find most concerning about the rise of vaping is that people who would’ve never smoked otherwise, especially youth, are taking up the habit . . .  It’s one thing if you convert from cigarette smoking to vaping. It’s quite another thing to start up nicotine use with vaping. And, it often leads to using traditional tobacco products down the road.

When Janet Woodcock testified before the House Subcommittee on Economic and Consumer Policy, she said protecting the youth of the US from the dangers of tobacco products was among the FDA’s most important responsibilities. “We are taking aggressive steps to make sure tobacco products are not being marketed or sold to kids.” After describing the FDA’s efforts to regulate ENDS (electronic nicotine delivery systems), and the agency’s actions to prevent youth access and use of these products, she said: “We still have much to accomplish and will continue to take strong action to protect youth and monitor the effectiveness of our actions.” Given the concerns noted here and in the linked articles, let’s hope that strong action will include the end of some ENDS products that have been clearly soliciting youthful consumers like Juul.

For more information on concerns with vaping and ENDS, see: “The Ticking Time Bomb of Vaping,” “Priming Young Adults with Vaping” and “Not the End of Smoking.”

11/24/20

Juul’s Empty Harm Reduction Rhetoric

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Juul Labs announced on September 3rd that it would be reducing its workforce, allegedly because of the coronavirus pandemic. According to The Wall Street Journal, that will be over half its remaining employees. Earlier this year Juul cut approximately one-third of its workers and stopped sales of its vaporizers in several countries. The September announcement came one day after Washington State filed suit against Juul, alleging the company designed its products to appeal to teens: “Upon the launch of the device, the company flooded social media with colorful ads of young-looking models and pushed fruit and dessert flavored products.”

The Juul Labs announcement of the cutbacks said it was trying “to place the company on a pathway to fulfill its mission by earning trust of key stakeholders while combating underage use.” Throughout 2020 the company said they had continued to carefully evaluate how to allocate its resources, in an evolving category (i.e., vaping devices) lacking in trust. “The global pandemic and ongoing economic crisis have thrown in a level of uncertainty round the world for which we have to prepare.” They plan to prioritize their resources to execute their long-term, focused approach seems to be an attempt to position Juul as a harm reduction product for adult smokers. Juul said these investments will not provide short-term revenue, but they will help the company earn trust and “build a company for the long term to advance the potential for harm reduction for adult smokers and combat underage usage.”

As such, we will be making a significant global reduction in force, and we will be exploring the possibility of exiting a variety of markets in EMEA and APAC that have not provided the kind of return necessary given the cost to continue investing in the market. In any potential new market, we would ensure that we can have science and evidence-based conversations with stakeholders before entering and that vapor products can effectively compete with combustible cigarettes.

Marketing Juul’s e-cigarette as a harm reduction tool for adult smokers may be part of the company’s new marketing strategy, but it also seems this claim was revisionist history of its earlier approach. In January 2019, The New York Times published, “Juul’s Convenient Smoke Screen,” referred to Juul’s TV advertising campaign, “Make the Switch,” as a “new pitch.” It had just taken in a $12.8 billion investment from Altria, the giant tobacco company behind Marlboro. “Now, after making billions of dollars and joining forces with Big Tobacco, Juul is billing itself as a public-health crusader.” There is evidence suggesting Juul Labs did not always have a public health agenda and cannot even enforce no vaping regulations within its own headquarters.

In 2018, Juul Labs told its employees that California-based employees can no longer vape at their desks, enforcing a 2016 California law that banned e-cigarettes in the workplace. But even though the company banned vaping in compliance with state and local laws, employees continued to use their e-cigarettes as their desks. One employee said it was like something straight out of the TV show Mad Men: “Just replace the cigarettes with e-cigarettes.” While some employees hide their Juuls in sweater sleeves, The Wall Street Journal reported the company’s co-founders and others continued to do it openly. “Even the threat of being fired after a fourth vaping offense hasn’t seemed to have done much.” If Juul Labs can’t stop its own employees from vaping at its offices, so how can it credibly pursue a market position as a harm reduction product?

A research and development engineer who helped create the original Juul device said the company didn’t think a lot about addiction because they were not trying to design a cessation product. “Anything about health is not on our mind.” That R&D engineer is still with Juul. In other early interviews, James Monsees, the co-founder and chief-product officer of Juul, played down the idea of a public health mission. In a 2014 interview posted on YouTube, he said the company was not an activist company. “If you don’t like what we’re making better than cigarettes, then have a cigarette, that’s fine.” The impression left is that Juul was presenting its pod as an alternative to cigarettes.

Monsees admitted the company had been forced to be cautious about its marketing. Federal regulations forbid it from promoting its device as a smoking cessation tool, but permits Juul to claim it is a “switching product” for smokers. He said in the January 2019 NYT article that since 2005 he and Adam Bowen, the other co-founder of Juul, have been focused on creating a product to help people switch away from combustible cigarettes. That is a subtle, but different goal than seeing Juul as a harm reduction product. The co-founders’ graduate thesis presentation pitched vaping as a healthier substitute for cigarettes. Interestingly, James Monsees announced his plan to step down as an advisor and board member of Juul Labs in March of 2020; and the YouTube video in which he said Juul Labs was not an activist company has been removed.

Few of the company’s early ads mentioned the risks of cigarettes or advocated for smokers to switch. Instead, they voiced how “Smoking evolved” and how it’s vaping device was “built to satisfy.” There was even a “launch party.” The president of the antismoking advocacy group, Campaign for Tobacco-Free Kids, said Juul’s ad campaign was little more than a P.R. effort aimed at lawmakers and regulators. “Juul has engaged in all the traditional tactics of a company that is trying to fend off meaningful regulation, rather than actually change their behavior . . . That is classic Big Tobacco.”

Juul’s attempt to convince the public it became a teen sensation by accident is disingenuous (See “Not The End Of Smoking”).  Juul products has been facing significant scrutiny for concerns over their health risks and marketed to young people for some time. Drugwatch reported there were currently 758 Juul lawsuits from around the U.S. The cases represent both class action lawsuits and personal injury cases, and the litigation is expected to continue to grow. Many of the lawsuits claim Juul marketed to minors, but the company denies this. “Most of the initial lawsuits in the mass litigation were filed before reports of widespread vaping-related lung injuries and deaths began coming up in mid-2019.”

The first wrongful death lawsuit was filed in October of 2019. A former senior vice president at Juul claimed he was fired after he raised the alarm when 1 million contaminated, mint-flavored Juul pods were shipped to retailers and consumers. He also claimed the company repeatedly sold expired products over his protests. A pair of Alabama college students filed suit in 2019 claiming they developed serious lung problems from vaping Juuls. As of August 2019, the FDA has identified 127 reports of vaping-related seizures or neurological symptoms.

Seizures are a known side effect of nicotine toxicity. “But many teens don’t realize nicotine is an e-cigarette danger.” When Juul e-cigarettes were first on the market, they delivered almost two to five times more nicotine than other e-cigarettes. Maxwell Berger’s lawsuit claimed the massive stroke that left him with a speech impediment, paralysis on his left side and a loss of vision in each eye before he turned 20 was the result of smoking two-Juul-pods-a-day.

Washington State filed suit against Juul Labs on September 2, 2020 alleging the company designed its product to appeal to underage consumers and was deceptive about the addictiveness of its product. Washington State Attorney General Bob Ferguson also claimed Juul misled consumers by not mentioning their cigarette pods contained nicotine. A 2018 survey by Truth Initiative found that 63% of Juul users did not know the product contained nicotine. Robin Koval, CEO and president of Truth initiative, said:

Unfortunately, young people are unaware that JUUL packs a powerful nicotine punch with a single cartridge equal to an entire pack of cigarettes. This escalates the urgency for Food and Drug Administration FDA) regulation and public education regarding the risks for young people.

In 2020, all health-related concerns appear to have some sort of a connection to the COVID pandemic and that is true for e-cigarettes as well. In “Vaping Links to Covid Risk Are Becoming Clear,” The New York Times said experts have warned since the start of the pandemic that the coronavirus, a respiratory pathogen, likely capitalizes on the damaged lungs of smokers and vapers. Doctors and researchers are beginning to pinpoint how smoking and vaping seem to boost the virus’s ability to spread from person to person, infiltrating the lungs and sparking some of COVID-19’s worst symptoms. Doctor Stephanie Lovinsky-Desir, a pediatric pulmonologist at Columbia University, said: “I have no doubt in saying that smoking and vaping could put people at increased risk of poor outcomes from COVID-19.”

While several studies have found smoking can more than double a person’s risk of severe COVID-19 symptoms, the data on vaping and COVID are just beginning to emerge. A team of researchers reported in the Journal of Adolescent Health that a COVID-19 diagnosis was five times more likely among young adults who vape and seven times more likely among dual users—those who vape and smoke cigarettes. “Youth using e-cigarettes and dual-users of e-cigarettes and cigarettes are at greater risk of COVID-19. Given the predominance of e-cigarette use among U.S. youth, our investigation informs public health concerns that the ongoing youth e-cigarette epidemic contributes to the current COVID-19 pandemic.”

Our findings from a national sample of adolescents and young adults show that e-cigarette use and dual use of e-cigarettes and cigarettes are significant underlying risk factors for COVID-19 that has previously not been shown. The findings have direct implications for health care providers to ask all youth and COVID-19–infected youth about cigarette and e-cigarette use history; for parents, schools, and community-based organizations to guide youth to learn more about how e-cigarettes and dual use affect the respiratory and immune systems; for the Food and Drug Administration to effectively regulate e-cigarettes during the COVID-19 pandemic; and for the development and dissemination of youth-focused COVID-19 prevention messaging to include e-cigarette and dual use.

A study published in 2018 did not find switching to ENDS (electronic nicotine delivery systems) helped adult smokers quit. Juul Labs marketing did target youthful users, as one look at the youthful-looking models in the above link “early ads” will show. And Juul’s harm reduction rhetoric is empty, as it can’t even rein in its own employees.

02/18/20

The Armageddon of Juul

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This past year was a terrible one for Juul. In December of 2018 the NIDA-funded Monitoring the Future (MTF) survey revealed that the percentage of students who reported vaping nicotine during the past 30 days doubled among 12th graders (from 11% to 21%) and among 10th graders (from 8% to 16%). The lead author of the study said the policies and procedures in place were not working to prevent youth vaping. “We need new policies and strategies, such as the FDA’s actions announced last month to curb the sales of the JUUL-branded vaping devices.” Two studies published in the Journal of the American Medical Association found that 27.5% of high school students reported current use of e-cigarettes, and more than half who vape used Juul. “‘Juuling’ has become synonymous with vaping for some teens.”

In November of 2018 Juul Labs CEO Kevin Burns announced an action plan that stopped selling some Juul flavor pods at the retail store level (Mango, Fruit, Crème and Cucumber), leaving only Menthol and Mint flavors. They shut down social media accounts with Facebook and Instagram, saying, “By deterring social media promotion of the JUUL system by exiting our accounts, we can better prevent teens and non-smokers from ever becoming interested in the device.” There is an embedded video explaining the lengths Juul Labs planned to go to prevent teen access to their products.

Juul Labs then launched a multimillion-dollar ad campaign attempting to rebrand itself as a stop-smoking aid for adults, spending $11.8 million on TV ads in the first four months of 2019. The ads avoided key word associated with FDA-approved smoking aids, such as “quit,” “addiction” and “health.” Instead, the company’s ads referred to “switching,” to Juul to get a nicotine “fix.” Juuling was said to be an alternative to smoking. The Atlantic noted how Juul seemed to be following a familiar marketing strategy, one used by Big Tobacco.

Throughout the 20th century, as warnings about the health risks of cigarettes arose, tobacco companies repeatedly found new ways to downplay concerns and advertise their products as healthy options. When their claims were refuted by evidence, they traded them out for new claims.

No e-cigarette, including Juul, has been approved by the FDA to help smokers quit, and there is even a disclaimer to that effect on Juul’s website. “I think the Juul ads are very carefully written and lawyered to confuse the public,” said Stan Glantz, a tobacco control researcher at the University of California San Francisco. A letter from the American Heart Association, the American Academy of Pediatrics and four other groups said:

Juul, a product that FDA has found to be largely responsible for the current epidemic of youth usage of highly addictive e-cigarettes, is being advertised and marketed on a massive scale as a smoking cessation product, without the required review and approval by FDA.

In Europe, nicotine levels are capped and advertising is tightly restricted. Britain and other European countries have promoted e-cigarettes as a reduced-risk product to smokers. They also ban most e-cigarette ads on television, newspapers, magazines and websites. By contrast, the FDA permits marketing across all these requiring the ads carry a single warning message: “This product contains nicotine. Nicotine is an addictive chemical.”

There was also a surge of severe lung illnesses linked to vaping. By December 17, 2019, the CDC reported 2,506 hospitalized lung injury cases associated with vaping from all fifty states, and 54 confirmed deaths. Vitamin E acetate was identified as a chemical of concern among people with lung injury (EVALI) cases. The FDA found that THC was present in most samples tested, and most patients reported a history of using THC-containing products. The agency suggested adults who continued to use e-cigarette or vaping products should carefully monitor themselves; and those who do not currently use tobacco products should not start using e-cigarette products: “There is no safe tobacco product.”

Big Tobacco wanted to get a piece of Juul. In December of 2018, the tobacco giant Altria invested $12.8 billion for a 35% nonvoting stake in Juul Labs, with the ability to appoint one director to the board. They appointed K.C. Crosthwaite, Altria’s chief growth officer. The Motley Fool reported that upon regulatory approval, Altria’s nonvoting shares will automatically convert into voting shares and the tobacco company then had the right to appoint a third of Juul’s directors. Among other provisions, Altria would also be able to sell its shares on the market if Juul has an initial public offering. Companies exchanging nonvoting shares for voting shares in an acquired company are required to tell the FTC about it.

Meanwhile, Juul was trying to stay ahead of what was looking like an Armageddon of federal regulation for the industry. In a CNBC documentary, Juul CEO Kevin Burns said he would tell the parents of teens addicted to Juul products, he was sorry: “First of all, I’d tell them that I’m sorry that their child’s using the product.” He went on to say Juul was not intended for them. “I hope there was nothing that we did that made it appealing to them. As a parent of a 16-year-old, I’m sorry for them, and I have empathy for them, in terms of what the challenges they’re going through.” In August of 2019, Burns told Tony Dokoupil on CBS This Morning, not to use their product, telling him, “Don’t use Juul.” Then at the end of September of 2019, Juul Labs announced Kevin Burns would resign as CEO and be replaced by K.C. Crosthwaite.

In a statement announcing that Altria was moving ahead with notifications of its conversion, the company said: “Altria continues to believe that its investment and the services Altria has agreed to provide JUUL will promote competition and have long-term benefits for adult smokers. Altria continues to anticipate that the conversion of its JUUL shares will occur as planned.” When the move is completed, Altria will have much more control over the direction Juul takes. Juul should be in a much better position to meet regulatory requirements because it will have Altria to help it meet the government’s expectations.

The New York Times reported that in changing its leadership, Juul was looking to Big Tobacco for its survival as it faces a federal criminal inquiry, new bans on some of its products, and multiple state and federal investigations into its marketing practices. In announcing its change of leadership, Juul also said it would not fight a proposal to ban most flavored e-cigarettes, which would have a seriously negative effect on its domestic sales. The company also said it would end its marketing campaign, “Make the Switch,” which the FDA said could be construed as an illegal effort “to portray its e-cigarettes as safer than traditional cigarettes.”

Within the last week alone, several television networks decided to stop broadcasting Juul’s ads; Massachusetts announced a four-month ban on the sale of all vaping products; Rhode Island announced a ban on flavors; Walmart said it would stop selling all e-cigarettes; and the F.D.A. announced it had opened a criminal inquiry into the supply chain of vaping products and devices. The Federal Trade Commission also has been investigating Juul’s marketing practices. And the United States attorney for Northern California opened a criminal investigation into the company, a development first reported by The Wall Street Journal.

This anticipates a regulatory face-off at the FDA in May of 2020 when the agency will determine whether e-cigarettes can remain on the domestic market. Juul’s new CEO said this may drive the market for e-cigarettes overseas. At an all-hands meeting at Juul headquarters, Crosthwaite told employees, “International expansion continues to be a huge opportunity given the number of smokers around the world.” But India said it would ban the sale of e-cigarettes, and the attempt to enter the Chinese market fell flat when the country’s tobacco regulator issued a notice asking e-commerce platforms and businesses to shut online stores that sell e-cigarettes.

At the end of October, The Motley Fool said Altria wrote down its Juul investment by $4.5 billion, reflecting how the company sees recent events impacting Juul’s sales and earnings. Altria’s CEO, Howard Willard said in a conference call with analysts, “Certainly in the range of scenarios when we made our investment in Juul, we did not anticipate this dramatic of a change in the e-vapor category.” For the time being, Altria is standing with Juul: “Despite this impairment charge, we remain committed to Juul’s success.”

Nevertheless, former FDA Commissioner Scott Gottlieb said in November of 2019 he thought Juul Labs’ products should be removed from the market, citing the above two studies published in the Journal of the American Medical Association. “It’s very clear that Juul can’t keep their products out of the hands of kids. . . . What’s driving the youth use is primarily Juul.” He said they’ve hooked a lot of kids. Following the study, Juul halted sales of its mint flavor, saying “these results are unacceptable and that is why we must reset the vapor category in the U.S. and earn the trust of society by working cooperatively with regulators, Attorneys General, public health officials, and other stakeholders to combat underage use.” K.C. Crosthwaite said Juul would support any FDA flavor policy and a regulatory process to get its nicotine pods cleared for sale in the US.

But is it too little, too late?

10/15/19

The Ticking Time Bomb of Vaping

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The clouds for the coming storm of adverse effects with e-cigarettes began to gather in the spring of 2019. Time Magazine reported the FDA was alerting Americans that vaping may be associated with seizures. Then in late May, researchers at the Stanford University School of Medicine published a study warning that the flavoring liquid of e-cigarettes may increase the risk of cardiovascular disease. After there was a report in the New England Journal of Medicine about an e-cigarette exploding in a teen’s mouth, reports of adverse effects began to fall all summer. The NEMJ said the teen had a circular puncture to the chin, extensive lacerations in his mouth, multiple disrupted lower incisors, a mandibular fracture and other injuries.

By late summer, the reports of possible cases of severe respiratory illnesses among people vaping more than doubled. Five people had died. In early September, the CDC suggested people should avoid using e-cigarettes. The NEMJ said e-cigarette products containing THC were the most commonly reported, in 84% of the study’s patients. But 17% of patients reported using only nicotine-based products, and 44% reported using both THC-based and nicotine-based products.

The findings in this report support several public health recommendations issued by the CDC. Since no single product or substance has been associated with the illness, persons should consider not using e-cigarettes while this investigation is ongoing, especially those purchased from sources other than authorized retailers (e.g., e-cigarette products with THC) and those modified in a manner not intended by the manufacturer. Adult smokers who are attempting to quit should consult with their health care provider and use proven treatments. Irrespective of these findings, e-cigarettes should never be used by youths, young adults, pregnant women, and adults who do not currently use tobacco products.

As of October 1, 2019, the CDC reported there were 1,080 lung injury cases associated with e-cigarette or vaping products from 48 states and 1 US territory. There were 18 confirmed deaths in 15 states. All patients reported a history of using e-cigarette or vaping products. Most said they had used THC-based products. Sixteen percent of patients were under 18; 21% were 18 to 20 years old. “No single product or substance has been linked to all lung injury cases. More information is needed to know whether a single product, substance, brand, or method of use is responsible for the outbreak.” See the CDC link for data on symptom onset and hospital admission with lung injury peaking in mid-August to early September.

According to NPR, the CDC’s principle deputy director, Dr. Anne Schuchat said: “We’re worried that there are plenty of risky products still out there. . .  That’s one of the reasons we’ve intensified our warnings.” She said it was essentially impossible to know what is in the e-cigarette or vaping product you are getting, especially the THC-containing products. “The data we are getting does not suggest this has peaked.” She added that these are serious injuries in the lung, “and we don’t know how well people will recover from them, whether lung damage may be permanent.”

The Wall Street Journal reported experts think the symptoms are sparked by an inflammation or injury in the lungs from a chemical exposure. Researchers at the Mayo Clinic published a review of lung biopsies from 17 patients and said the injuries seemed more like the consequence of inhaling toxic chemicals rather than an oil. However, some of the earlier cases were diagnosed as lipoid pneuma, “which is a result of inhaling a fat or oil into the lungs.” Aside from the vaping link, federal officials are not sure of the exact cause of the outbreak. See the WSJ link for a short video on how it appears to be related to black market THC vapes.

The New York Times reported that as of October 4th, there were 21 confirmed deaths in 18 states. See the following map by the New York Times for cases of vaping-related lung illness and vaping-related deaths.

Dr Howard Zucker, the New York State health commissioner, said this was a public health emergency:

It is undeniable that the vaping industry is using flavored e-cigarettes to get young people hooked on potentially dangerous and deadly products. While the court’s ruling temporarily delays our scheduled enforcement of this ban, it will not deter us from using every tool at our disposal to address this crisis.

Reflecting on his blog about the vaping illnesses and deaths, William White, the Emeritus Senior Research Consultant of Chestnut Health Systems, said new technologies that increase the efficiency of drug consumption by altering per episode and lifetime drug dosage, drug purity, or the method of drug administration may require “a fundamental rethinking of the risks associated with particular drugs.”

While the toxic effects of new drugs and new ways of using known drugs are usually identified early in their social emergence, the nightmare scenario would be a Trojan Horse that possessed few if any short term negative effects but devastating effects linked to long-term use. That is precisely the scenario that forced a radical rethinking of the effects of smoking tobacco over the past century. When toxic drug effects become quickly apparent before widespread use, mass public health damage can be minimized. In the case of tobacco smoking, short term studies would not have revealed smoking as the ticking time bomb that it is. We must be vigilant in identifying other drugs and patterns of drug consumption that may share a similar trajectory.

White’s concluding paragraph said those in the forefront of dealing with addiction have a unique opportunity to identify these threats early in their emergence. When we see them, “we can communicate what we are observing to public health and community leaders, and by so doing, arouse action to reduce the numbers of people exposed to such threats as well as get people already exposed the help they need as quickly as possible.” So, here is something new about vaping that just appeared this morning, as I was completing this article on October 8, 2019: “Vaping nicotine linked to lung cancer.”

News, Medical reported how a team of researchers at New York University School of Medicine caused mice to develop lung cancer. Yes, it is just an initial study with mice, but remember that if vaping is a relatively new way of using nicotine, research into the adverse effects of vaping is even newer. Mice studies are where researchers begin to investigate the problems. The study, “Electronic-cigarette smoke induces lung adenocarcinoma and bladder urothelial hyperplasia in mice” said that since given the fact that epidemiological data on the relationship between e-cigarettes (ECS) and human cancer may not be known for another ten years, the carcinogenicity of ECS was tested in mice. The researchers found that mice exposed to e-cigarettes for 54 weeks developed lung adenocarcinomas (9 of 40 mice, 22.5%) and bladder urothelial hyperplasia (23 of 40 mice, 57.5%). “We showed that ECS exposure of mice induces lung cancer and bladder urothelial hyperplasia.” The lead author of the study, Moon-shong Tang, said to News, Medical:

Tobacco smoke is among the most dangerous environmental agents to which humans are routinely exposed, but the potential of E-cig smoke as a threat to human health is not yet fully understood. Our study results in mice were not meant to be compared to human disease, but instead argue that E-cig smoke must be more thoroughly studied before it is deemed safe or marketed that way.

Then on October 11, 2019, an article was published in Nature that reported on various studies of adverse consequences of e-cigarette use. Some researchers are focusing on general lung damage and inflammation from toxic chemicals, others are concentrating on vitamin E acetate, an oily chemical suggested as a cause of the vaping illness. One researcher cautioned against hoping for quick answers; her initial findings took three and a half years to complete. The chief medical officer of the American Lung Association said science would eventually win, “But I don’t think it’s going to be as soon as people would like.”

Other researchers are working to categorize the chemicals contained in e-cigarettes. But the thousands of products and the culture of users who readily modify e-cigarettes and their contents makes this “a tough nut to crack.” One researcher said vapers are altering everything from how hot their e-cigarettes get to what chemicals are included in vaping cartridges, including in one instance, liquid Viagra. In the meantime, the vaping illness has sickened about 1,300 US vapers and killed 26. Brandon Larsen, a pulmonary pathologist, said everything is so rapidly evolving, that “I could tell you something today and next week it could be totally wrong.”

William White is right. We must remain vigilant to recognize potential long-term adverse effects with e-cigarettes in order to minimize mass public health damage. “It takes two decades or more for a life-time smoker to develop lung cancer. If tobacco smoke-induced lung carcinogenesis is a paradigm for e-cig carcinogenicity, then it will take at least another decade to have e-cig-related human lung cancer to show up.” It seems there is emerging evidence that the trajectory of e-cigarettes is leading us down the same path as tobacco cigarettes and it seems smoking e-cigarettes is a ticking time bomb. Do we really want to wait another ten years for the conclusive evidence of epidemiological data on the relationship between e-cigarettes (ECS) and human cancer before we take action to minimize the risk?

04/30/19

Not the End of Smoking

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America’s teens reported a striking increase in their vaping in the previous 12 months, from 27.8 % in 2017 to 37.3% in 2018. Reported vaping in the 30 days prior to the survey almost doubled among high school seniors, going from 11% in 2017 to 20.9% in 2018. Nora Volkow, the director of the National Institute on Drug Abuse (NIDA), said: “Teens are clearly attracted to the marketable technology and flavorings seen in vaping devices; however, it is urgent that teens understand the possible effects of vaping on overall health; the development of the teen brain; and the potential for addiction.” She went on to say research shows that teens who vape may be at risk of transitioning to smoking cigarettes.

The increase in vaping rates for 2017-2018 was consistent with the findings of the National Youth Tobacco Survey, which said e-cigarettes were the most commonly used tobacco product among U.S. middle school and high school students. The most selected reason for e-cigarette use was they were available in flavors like mint, candy, fruit or chocolate. The lead author for the Monitoring the Future study, which annually surveys 12th, 10th and 8th grade students, said in a letter to The New England Medical Journal the increases in the prevalence of vaping nicotine translated into roughly 1.3 million additional adolescents vaping.

Put in historical context, the absolute increases in the prevalence of nicotine vaping among 12th-graders and 10th-graders are the largest ever recorded by Monitoring the Future in the 44 years that it has continuously tracked dozens of substances. These results indicate that the policies in place as of the 2017–2018 school year were not sufficient to stop the spread of nicotine vaping among adolescents. The rapid entry of new vaping devices on the market, the latest example of which is the Juul, will require continual updates and modification of strategies to keep adolescents from vaping and its associated negative health effects.

Scott Gottlieb, the former commissioner of the FDA, who had been active in efforts to thwart this trend, sent 1,300 warning letters over the summer of 2018 to online and brick-and-mortar stores for selling e-cigarette products to underage consumers. He also sent out warning letters to five manufacturers, asking them to address the popularity of their products with underage consumers or risk the removal of “some or all of their flavored products.”  In the letter sent to Juul Labs, the FDA requested that within 60 days, “you provide a written response to this letter that includes a detailed plan, including specific timeframes, to address and mitigate widespread use by minors.” Giving suggestions for that plan, the letter said Juul Labs could:

  • Discontinue sales to retail establishments that have been subject to an FDA civil monetary penalty for sale of tobacco products to minors within the prior 12 months;
  • Develop or strengthen any internal program you have to check on retailers, and report to FDA the name and address of retailers that have sold products to minors;
  • Eliminate online sales, whether through Internet storefronts controlled by your company or other retailers, or provide evidence to demonstrate that your company’s online sales practices do not contribute to youth use of JUUL products;
  • Revise your current marketing practices to help prevent use by minors;
  • Remove flavored products from the market until those products can be reviewed by FDA.

Then unexpectedly, in the middle of his crusade against teen vaping, Scott Gottlieb resigned as the commissioner of the FDA, effective April of 2019. His stated intention was to spend more time with his wife and three daughters. He said: “There’s perhaps nothing that could pull me away from this role other than the challenge of being apart from my family for these past two years and missing my wife and three young children.” Gottlieb said the policies he initiated will move forward as planned, including the proposed restrictions recently announced on the sale of flavored e-cigarette products. The New York Times said retailers were on Capitol Hill lobbying against the FDA proposals. “Conservative groups and vaping trade associations also have come out in opposition, saying that the agency’s efforts to regulate the e-cigarette industry amount to government overreach.” Yet some public health advocates think the action steps were too late.

A December 2018 investigation reported in JAMA Network Open sought to estimate the concentration of tobacco-related toxins among e-cigarette users. Findings suggested that exclusive e-cigarette use resulted in measurable exposure to tobacco-related toxicants, generally at lower levels than with cigarette smoking. Dual users had higher concentrations of exposure to nearly all biomarkers when compared with cigarette-only smokers. “Several biomarkers measured in this study are metabolites of known carcinogens as well as respiratory, cardiovascular and/or reproductive/developmental toxicants.” The data clearly showed e-cigarette users were exposed to known tobacco-related toxicants.

Another study presented at the American College of Cardiology’s 68ith Annual Scientific Session shoed that adults using e-cigarettes are significantly more likely to have a heart attack, coronary disease and depression when compared to nonusers. The study’s lead author said: “Until now, little has been known about cardiovascular events relative to e-cigarette use. These data are a real wake-up call and should prompt more action and awareness about the dangers of e-cigarettes.”

This study found that compared with nonusers, e-cigarette users were 56 percent more likely to have a heart attack and 30 percent more likely to suffer a stroke. Coronary artery disease and circulatory problems, including blood clots, were also much higher among those who vape — 10 percent and 44 percent higher, respectively. This group was also twice as likely to suffer from depression, anxiety and other emotional problems.

Scott Gottlieb said that if the 2019 National Youth Tobacco Survey shows another spike in teen use of e-cigarettes, “We’re going to be back making new policy in the fall.” One of those possible changes could be taking all pod-based e-cigarettes off the market. “At some point, the youth use of those products becomes so intolerable that they have no redeeming public health value, and we’ll just have to sweep the market of those products. And that includes Juul. Those are the products being abused by the children.”

In a statement released on Wednesday, March 13, 2019, Juul Labs said they are committed to reducing youth usage of their products, while preserving their opportunity to “eliminate combustible cigarettes.” They noted how in November of 2018 they stopped the sale of flavored Juul pods to retail stores, strengthened their retail compliance and secret shopper program, enhanced their online age-verification and exited their Facebook and Instagram accounts.

We support category-wide action including the responsible, restricted sale of flavored products and will review today’s draft guidance as we continue to work with FDA, state Attorneys General, local municipalities, and community organizations as a transparent and responsible partner in combating underage use.

So, what is the bottom line on the risks of e-cigarettes for teens? The CDC has a page of “Quick Facts on the Risks of E-Cigarettes.” It said the use of e-cigarettes in not safe for teens and young adults. They contain nicotine, which is highly addictive “and can harm the adolescent brain development.” Young people who use e-cigarettes may also be more likely to smoke cigarettes in the future, which points to the motive underlying Gottlieb’s crusade.

Finally, what about Juul Labs desire to use its e-cigarette to eliminate combustible cigarettes? One of the strongest arguments for vaping is that it can help people taper off from their addiction to tobacco smoking. A group of researchers sought to generate evidence on the ‘real world’ use of e-cigarettes on the quit rates of adult smokers. They recruited 1284 current, established smokers and then re-contacted them after a year. Although 16% had stopped smoking, they found no evidence that electronic nicotine delivery systems (or ENDS) were helping adults quit “at a higher rate than smokers who did not use these products, despite ENDS users being more likely to make a quit attempt.” In other words, they did not put an END to smoking.

Our study suggests that use of current ENDS products in real world conditions do not seem to improve the chances of quitting for smokers, and, under the current landscape, may not be the disruptive technology that increases the population quit rate and reduces the harm of combustibles. Additional steps may be needed to spur innovation to create low-harm and low-risk products that adequately deliver nicotine, address the misperceptions of relative harm of ENDS compared to cigarettes, and encourage cessation and complete switching from combustibles to low-harm and low-risk products among smokers who do not want to quit smoking.

Changes to their design, to how e-cigarettes are marketed and regulated may be too slow and ineffectual to lead to the above changes on their own, according to the lead author of the ‘real world’ study published in PLoS One. But for now, it seems e-cigarettes are more likely to become an add-on to smokers than an effective tool to stop smoking. “People who use both tobacco and e-cigarettes are actually less likely to quit smoking than people who only stick to tobacco.”

04/9/19

Not JUULing Around

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Under its Commissioner Scott Gottlieb, the FDA has taken several steps to address what it sees as an ‘epidemic’ of youth e-cigarette use. On September 12, 2018, it issued more than 1,300 warning letters and fines to retailers who illegally sold JUUL and other e-cigarette products to minors. This was part of its Youth Tobacco Prevention Plan. Twelve warning letters were also issued, as some retailers had ignored previous warning letters issued in May of 2018. One of the FDA’s potential actions was to remove some or all of their flavored products from the market and require a premarket authorization from the agency. It then announced a public hearing was to be held on December 5, 2018 “to discuss the agency’s efforts to eliminate youth e-cigarette use.”

In an embedded YouTube video, JUUL CEO Kevin Burns said their mission was to “improve the lives of the world’s one billion smokers and eliminate cigarettes.” Their intent was never to have youths use JUUL, “but they are.” The numbers tell them underage use of e-cigarette products is a problem they must solve. “For us to successfully fulfill our mission of helping adult smokers, we must be trusted – and we must earn that trust. That starts with action, not words.”

He then announced JUUL”S intent to stop selling flavored products  (Mango, Fruit, Crème and Cucumber) in retail stores and only make them available online. They also limited online customers to two devices and fifteen JUUL pod packages per month; and no more than ten devices per year. They planned to strengthen their retail compliance and shut down their social media accounts: “By deterring social media promotion of the JUUL system by exiting our accounts, we can better prevent teens and non-smokers from ever becoming interested in the device.”

We are implementing this plan starting today [November 13, 2018]. We will be a transparent, engaged, and committed partner in this effort with FDA, state Attorneys General, local municipalities, and community organizations. We thank Commissioner Gottlieb for his ongoing leadership on this critical issue. JUUL Labs hopes the components of our plan are implemented industry-wide. If implemented across the category, these actions will have the greatest impact in restricting access and ultimately decreasing underage use, along with 21+ laws on all tobacco products. On that point, JUUL Labs will not only continue to support Tobacco 21, we will actively pursue it by drafting legislation, funding advocacy campaigns, and engaging with lawmakers.

Sounds like JUUL Labs is trying to do the right thing, doesn’t it? Now see this August 10, 2018 video by Vox, “How Juul made nicotine use go viral.” It announced JUUL has taken over about 70% of the retail e-cigarette market. The technological simplicity of JUUL means it looks more like a “cool gadget and less like a drug delivery device.” The JUUL co-founders met at Stanford Design School and one of them worked as a design engineer at Apple. No wonder it’s called “the iPhone of E-cigs.”

The video said current marketing today for JUUL is focused on adult ex-smokers. “But when JUUL first launched, their marketing looked a lot different.” Those ads bear a striking similarity to old cigarette ads. “Both marketed relaxation, sharing, travel, freedom and sex appeal.” Now it is illegal for cigarette brands to use these suggestive advertising themes. But for e-cigarette manufacturers who had products on the market before 2016, “those strategies are still unregulated.” JUUL launched in 2015.

In “Juul’s Convenient Smoke Screen,” The New York Times reported that in 2015, a research and development engineer for JUUL said: “We don’t think a lot about addiction here because we’re not trying to design a cessation product at all. . . .  Anything about health in not on our mind.” James Monsees, JUUL’s co-founder and chief product officer said the company was forced to be careful about its marketing. Under federal regulations it is permitted to bill its device as a “switching product” for smokers, “but not as a smoking cessation or health device.” Although JUUL ran ads in the past it would not do today, he said, it always focused on eliminating cigarettes. “Since 2005, we have been focused on creating a product to help people switch away from smoking combustible cigarettes — the number one cause of preventable death in the world.”

But Juul’s public marketing told a different story. Few of the company’s early ads made any mention of cigarettes’ risks, or advocated for smokers to switch; most were focused on playing up vaping’s cool factor. As recently as 2017, the front page of the company’s website said nothing about switching from cigarettes at all, only that the Juul offered an “intensely satisfying vapor experience.”Recently, Juul — now equipped with an army of lobbyists and a slick communications team that includes a former White House spokesman — has studiously revamped its image. Glossy profiles have been written about the company’s “lifesaving mission” and Juul’s new chief executive, Kevin Burns, has gotten on message, emphasizing the company’s focus on adult smokers.

The president of the antismoking advocacy group Campaign for Tobacco-Free Kids, Matthew L. Myers, saw JUUL’s new ad campaign as a P.R. effort aimed at lawmakers and regulators. “”Juul has engaged in all the traditional tactics of a company that is trying to fend off meaningful regulation, rather than actually change their behavior,’ Mr. Myers said. ‘That is classic Big Tobacco.’”

Juul wants you to believe that it became a teenage sensation entirely by accident, that its products were only ever meant for adult smokers and that taking billions of dollars from Big Tobacco is consistent with the values of a company that has always put a priority on health over profits. The truth is much hazier than that.

There was a study published in JAMA Network Open on October 19, 2018 that said adolescent use of pod-based e-cigarettes was increasing rapidly, “and adolescents and young adults report corresponding misperceptions and lack of knowledge about these products.” The researchers reported that only 25% knew all JUULs contained nicotine. Adolescents and young adults were recruited from 10 high schools in California from July 13, 2014 through October 11, 2015. Only 2.5% reported exclusive use of JUULs; 25.2% reported using three products: pod-based e-cigarettes, other e-cigarettes and cigarettes.

The 3 most concerning insights from the data presented here are the high prevalence of co-use and polyuse of pod-based e-cigarettes with other e-cigarettes and traditional cigarettes and the higher proportion of participants who reported past 30-day use together with the much higher frequency of use reported for pod-based e-cigarettes vs other e-cigarettes. These findings point to the potential for greatly increased harm for adolescents and young adults associated with the use of pod-based e-cigarettes, as their still-forming brains are particularly vulnerable to the effects of nicotine, with increased earlier exposure to nicotine being associated in a dose-response manner with deleterious health effects.

Then there was the announcement on December 19, 2018 that Altria, the company that owns Marlboro and is the nation’s largest maker of traditional cigarettes, bought a 35% stake in JUUL Labs for $12.8 billion. Part of the deal was a $2 billion bonus, which will be split among JUUL’s 1,500 employees. According to The New York Times, JUUL Labs will now have access to Altria’s  “deep lobbying pockets” and its more experienced government relations team. Altria spent more than $7 million on lobbying in 2018, while JUUL Labs spent almost $900,000.

The New York Times reported how the “F.D.A Accuses Juul and Altria of Backing Off Plan to Stop Youth Vaping.” Scott Gottlieb drafted letters to both companies criticizing them for “publicly pledging to remove nicotine flavor pods from store shelves, “while secretly negotiating a financial partnership that seems to do the opposite.” In October Altria agreed to stop selling pod-based e-cigarettes until it received FDA permission “or until the youth problem was otherwise addressed.”

But the new deal commits the tobacco giant to dramatically expanding the reach of precisely those types of products, by giving Juul access to shelf space in 230,000 retail outlets where Marlboro cigarettes and other Altria tobacco products are sold. (Juul currently sells in 90,000 stores.)It is a development that startled the F.D.A., which in September had threatened to pull e-cigarettes off the market if companies could not prove within 60 days that they could keep the products away from minors. Altria, Juul and three tobacco companies sent the detailed plans spelling out how they would comply with the agency’s request. Now, those plans appear in jeopardy, Dr. Gottlieb said.

In an interview at the Brookings Institution, Gottlieb said the phenomenon of teen vaping was an “epidemic” and suggested Altria reneged on earlier promises to withdraw pod-based products from the market.  He said in October of 2018 he asked the e-cigarette industry for a plan to address teen vaping. Altria responded by giving the FDA a 15-16 page letter “saying that they would agree to withdraw their pod-based products voluntarily,” and further stating they would not put flavored products on the market until the FDA approved them. The company then withdrew some of its brands like MarkTen and Green Smoke, while at the same time investing in Juul Labs. Gottlieb said: “I continue to have concerns that some of the activities [Altria is] taking in the market are not necessarily consistent with what they’re telling us.” Then on March 5th, Scott Gottlieb resigned as the FDA commissioner. His last day was April 5th.

JUUL was looking more and more like Big Tobacco; and now it IS Big Tobacco!

03/19/19

Double Whammy of Teens Vaping Marijuana

© Sergey Nazarov | 123rf.com

The FDA recently announced there is a “growing epidemic of youth e-cigarette use” and held a hearing on December 5th to discuss efforts to eliminate teen e-cigarette use. Since 2014, the most commonly used method of consuming tobacco products among teens has been vaping—“used by 1.73 million (11.7 percent) high school students and 390,000 (3.3 percent) middle school students in 2017.” FDA Commissioner Scott Gottlieb expressed concern that a large pool of nicotine users is being created among school-age children. But that isn’t the only substance teens are smoking more. In JAMA Pediatrics a research letter said nearly one-third of middle and high school students are vaping marijuana.

USA Today reported the researchers found 8.9% of those surveyed said they had smoked marijuana in e-cigarettes. “Among those who reported vaping, nearly 1 in 3 high school students and about 1 in 4 middle school students reported using cannabis in the devices.”  Unless the manufacturers can prove they are trying to stop children and teens from using e-cigarettes, the FDA will stop the sales of flavored ones. “We’re going to have to take action.”

Gallup also reported that vaping is more prevalent among Americans who were under 30. While 9% of all Americans said they regularly or occasionally vape, 20% of those who were between the ages of 18 to 29 do so. This compared to 8% among those who were 30 to 64 years of age; and less than 5% among those 65 and over. See the following table.

Young people were less likely than those over 30 to believe vaping was risky; somewhat parallel to their views on marijuana. Twenty-two percent of those under 30 believe vaping was “very harmful” to your health, compared to at least 40% for every other age group. Notice how at the same time young people’s views about the health effects of traditional smoking was no different than older age groups’ views. See the following table.

There are several things that make vaping marijuana appealing to teens, according to Bonnie Halpern-Fisher. Vaping has less of an odor than smoking. And marijuana is increasingly easier to obtain, as it is legal in ten states for adults. Helpern-Fisher also expressed concern over the number of youth vaping marijuana. “You’re basically using it in a very strong form.” Teens face a special risk because their brains are still developing: “Youth are at a very vulnerable time.” See “Priming Young Adults with Vaping” for more on marijuana use and vaping among teens.

A small study in JAMA Network Open found that vaporized cannabis resulted in “significantly greater subjective drug effects, cognitive and psychomotor impairments, higher blood THC concentrations than the same doses of smoked cannabis.” They speculated the procedures in former studies enabled users to titrate their THC dose, while the current study required participants to self-administer a fixed amount of cannabis. “Therefore, holding THC dose constant, vaporizers appear to be a more efficient cannabis and THC delivery method, likely because with traditional smoked preparations, more THC is lost as a result of pyrolysis (combustion) and/or sidestream smoke.” The researchers concluded:

In this study, participants experienced dose-orderly increases in subjective drug effects, cognitive and psychomotor impairment, acute cardiovascular effects, and blood THC concentrations following inhalation of smoked and vaporized cannabis. Notably, vaporized cannabis produced greater changes in study outcomes relative to smoked cannabis. As the legal cannabis marketplace continues to expand, future studies should further explore the effects of vaporizers and other novel methods for cannabis administration in users with different degrees of experience with cannabis, as the pharmacokinetic and pharmacodynamic profiles will likely differ substantially across products and users.

However, the effects on cognitive functioning could be temporary in some cases. A meta-analysis by Scott et al., published in JAMA Psychiatry, found there was a “small but significant overall effect size for reduced cognitive functioning in adolescents and young adults” reporting frequent cannabis use. The studies requiring abstinence longer than 72 hours had a small, nonsignificant effect size. The researchers speculated that reported deficits could reflect residual effects from acute use or withdrawal.

Nevertheless, Gruber et al. said in “The Grass Might be Greener” there is a large body of evidence suggesting marijuana use was related to cognitive decrements, including deficits in verbal memory, attention and executive function. And while these deficits were found in adult marijuana users, they were more prominent in adolescent users, who were in the midst of neurodevelopment.  The deficits have also been linked to changes in brain structure and function. “Similar to studies of cognitive performance and brain structure, fMRI studies have revealed that earlier onset of MJ use is related to altered patterns of brain activation during tasks requiring cognitive control and inhibition.”

It seems that this poorer cognitive performance was due to the effects of THC (Δ9-tetrahydrocannabinol), while CBD (cannabidiol) has been shown to improve cognitive function. “In general, studies suggest that THC and CBD have opposite effects on cognition-related brain activation.” So they hypothesized that after 3 months of medical marijuana treatment, patients would demonstrate improved task performance and these changes would coincide with changes in brain activation patterns measured by fMRI.

Following 3 months of MMJ treatment, patients exhibited improved task performance and related alterations in frontal brain activation patterns during the completion of the MSIT, a measure of executive function and cognitive control, relative to pre-MMJ treatment. Within the cingulate cortex (CC), patients did not exhibit any significant pre-treatment activation during the Interference condition of the MSIT; however, after 3 months of treatment, robust activation was noted within this region. In fact, the magnitude of activation significantly increased over the course of treatment such that post-treatment activation patterns appeared more similar to that of healthy controls observed in previous studies. Activation within the frontal ROI was also notably increased following 3 months of MMJ treatment relative to pre-MMJ treatment. Taken together, these changes may be reflective of a potential “normalization” of brain function following 3 months of MMJ use.

There was also improved task performance and self-reported improvements in mood and quality of life, as well as reduced sleep disturbance and lower motor impulsivity. “It is possible that improvements in symptomatology (i.e., relief of symptoms, improved mood/sleep) are directly related to observed improvements in cognitive function and alterations in brain activation.”

While findings in this study show improvements in cognitive task performance, previous studies entirely focused on recreational (THC) marijuana users have reported decrements in cognitive performance. Among the factors that may account for this difference, Gruber et al. noted the majority of prior studies of recreational marijuana use included adolescent and young adult populations. Studies have overwhelmingly demonstrated that early onset of recreational marijuana use was related to poorer task performance and changes in brain function. Given that participants in their study were well-beyond the critical stages of neurodevelopment (mean age=50.64), “They are less likely to be vulnerable to the adverse neural effects of THC.”

The dangers then seem to be from recreational marijuana use—in other words from strains with higher THC and lower CBD levels. Early onset of recreational marijuana use also increases the adverse effects of cognitive decrements. When these factors are added to the FDA’s concern with the “growing epidemic of youth e-cigarette use,” there seems to be a double whammy to finding that nearly 1 in 3 high school students are vaping marijuana. They are in danger from increased exposure to nicotine and marijuana.

02/23/18

Priming Young Adults with Vaping

© Oleg Gavrilov | 123rf.com

The National Institute of Health announced that recent national survey research discovered that almost 1 in 3 (27.8%) 12th graders reported some kind of use of a vaping device in the past year, while the use of hookahs and regular cigarettes is declining. When asked what they thought was in the mist they inhaled, 51.8% said it was just flavoring, 32.8% said the mist contained nicotine, and 11.1% said they were smoking marijuana or hash oil. Nora Volkow, the director of NIDA, said: “We are especially concerned because the survey shows that some of the teens using these devices are first-time nicotine users.” Recent research suggests some of them could move on to regular cigarette smoking … or other drugs. And some additional research suggests many teens don’t actually know what is in the device they are using.

Monitoring the Future (MTF) is a yearly survey of 8th, 10th and 12th graders in school nationwide. The MTF survey is done by the Institute for Social Research at the University of Michigan for NIDA, the National Institute on Drug Abuse. When the survey asked about vaping over the past month, 11% of 12th graders reported vaping nicotine and 4.9% reported vaping marijuana. See the following chart from the NIH news release.

According to the CDC, e-cigarettes are now the most commonly used form of tobacco by youth in the U.S. Dual use, using both regular cigarettes and e-cigarettes, is also common among young adults 18-25. The reasons reported by young people for trying e-cigarettes include curiosity, taste and the belief they are less harmful than other tobacco products. Over 80% of teens and young adults who use e-cigarettes said they use flavored e-cigarettes.

Back in June of 2016 the FDA finalized a rule that extended its regulatory authority to all tobacco products, including e-cigarettes, cigars, hookahs and pipe tobacco. The rule requires health warnings and bans free samples. It also restricts youth access to newly regulated tobacco products by not allowing their sale to those younger than 18 and requiring a photo ID. Manufacturers will have up to two years to continue selling their products while they submit a new tobacco product application (and an additional year while the FDA reviews the application).

The rule will help prevent young people from starting to use these products, help consumers better understand the risks of using these products, prohibit false and misleading product claims, and prevent new tobacco products from being marketed unless a manufacturer demonstrates that the products meet the relevant public health standard.

If the new technology in e-cigarettes helps reduce toxicity compared to conventional cigarettes, encourages current smokers to switch completely and/or are not widely used by youth, they potentially could reduce disease and death. “But if any product prompts young people to become addicted to nicotine, reduces a person’s interest in quitting cigarettes, and/or leads to long-term usage with other tobacco products, the public health impact could be negative.” The FDA encouraged manufacturers to explore product innovations that would maximize potential benefits and minimize risks. The revised rule allows the FDA to further evaluate the impact of these products on the health of both users and non-users.

Psychiatric Times reported e-cigarettes were first developed and commercialized in China in 2003. They entered the US market in 2006. During their first ten years on the market, before the FDA ruling discussed above, advertising and sales of e-cigarettes increased exponentially every year. “While tobacco advertising has been banned from television and radio since 1970, e-cigarettes are promoted widely on these media channels, on the web, and in social media, with many ads reaching youth.” Mislabeling has been a problem with some products labeled as nicotine-free containing nicotine and others having higher concentrations of nicotine than labeled.

The evidence for e-cigarettes as a cessation aid to quit regular cigarette smoking is limited. Dual use of regular cigarettes and e-cigarettes is common. One study reported half of current smokers report regular use of e-cigarettes. A meta-analysis of twenty controlled studies found the odds of quitting cigarettes was 28% lower in individuals who used e-cigarettes. However only 2 randomized controlled trials have been done, and: “The quality of evidence was judged to be low grade, and in both trials, e-cigarettes with nicotine were no different in efficacy for quitting smoking than placebo (nicotine-free) e-cigarettes.”

So at this point in time, the evidence does not support the use of e-cigarettes as an aid to stop smoking regular cigarettes. It should be noted that the American Heart Association’s policy statement of e-cigarettes does not recommend their use. However, if a patient has tried and failed other cessation methods or is unwilling to try them, the AHA does recommend trying e-cigarettes for smoking cessation.

There is evidence that smoking e-cigarettes increases the risk of cardio vascular problems. Swedish researchers, in Antoniewicz et al., demonstrated that in healthy volunteers, ten puffs from an e-cigarette caused an increase in endotheial progenitor cells (EPSs) of the same magnitude as smoking one traditional cigarette. The average e-cigarette user takes 230 puffs per day, raising the prospect that prolonged use could result in serious health consequences. “These findings suggest that a very short exposure to ECV [e-cigarette vapor] caused a rapid EPC mobilization in blood, which may indicate an impact on vascular integrity leading to future atherosclerosis [hardening of the arteries].” A heart specialist for the European Society of Cardiology was quoted in the Daily Mail as saying: “It really surprises me that so little vapour from an e-cigarette is needed to start the heart disease ball rolling. It’s worrying that one e-cigarette can trigger such a response.”

Researchers at the University of Connecticut found evidence that e-cigarettes containing a nicotine-based liquid are potentially as harmful as unfiltered cigarettes in causing DNA damage. The study’s lead author said the results surprised him. “I never expected the DNA damage from e-cigarettes to be equal to tobacco cigarettes.” He was shocked the first time he saw the result, so he diluted the samples and ran the controls again. “But the trend was still there – something in the e-cigarettes was definitely causing damage to the DNA.”

Researchers at the University of North Carolina found that not only do e-cigarettes trigger the same immune responses as regular cigarettes, they also trigger some unique reactions. E-cigarette users uniquely showed significant increases with neutrophil-extracellular-trap (NET)-related proteins in their airways. “Left unchecked neutrophils can contribute to inflammatory lung diseases, such as COPD and cystic fibrosis.” The study also found that e-cigarettes produced negative consequences known to occur in regular cigarettes such as an increase of biomarkers of oxidative stress and activation of defense mechanisms associated with lung disease. They also found an over secretion of mucus secretions that have been associated with diseases like chronic bronchitis, bronchiectasis and asthma.

Another study by Eric and Denise Kandel, “A Molecular Basis for Nicotine as a Gateway Drug” has raised concerns with e-cigarettes as “pure nicotine-delivery devices.” Their study demonstrated that nicotine acted like a gateway drug for cocaine on the brain of mice, “and this effect is likely to occur whether the exposure is from smoking tobacco, passive tobacco smoke, or e-cigarettes.”

These results provide a biologic basis and a molecular mechanism for the sequence of drug use observed in people. One drug affects the circuitry of the brain in a manner that potentiates the effects of a subsequent drug.Although the typical e-cigarette user has been described as a long-term smoker who is unable to stop smoking, the use of e-cigarettes is increasing exponentially among adolescents and young adults. Our society needs to be concerned about the effect of e-cigarettes on the brain, especially in young people, and the potential for creating a new generation of persons addicted to nicotine. The effects we found in adult mice are likely to be even stronger in adolescent animals. Priming with nicotine has been shown to lead to enhanced cocaine-induced locomotor activity and increased initial self-administration of cocaine among adolescent, but not adult, rats. Whether e-cigarettes will prove to be a gateway to the use of combustible cigarettes and illicit drugs is uncertain, but it is clearly a possibility.

Don’t be too quick to dismiss the Kandels’ nicotine-gateway theory. They were doing basic research on the effects of nicotine on specific areas of the brain. Priming with nicotine enhanced the effects of cocaine in the nucleus accumbens. “Priming with nicotine appeared to increase the rewarding properties of cocaine by further disinhibiting dopaminergic neurons in the ventral tegmental area.” They only observed the priming effect of nicotine when mice were given cocaine at the same time as nicotine. For more on Denise Kandel’s gateway hypothesis see: “Rebirth of the Gateway Hypothesis.”