Electronic cigarettes (EC), or e-cigarettes as the cool kids like to say, are all the rage… and provoking rage, too. Supporters see a device that is a lot healthier than standard cigarettes and it happens to be a really useful smoking cessation aid, too. Those opposed detect a whiff of the early- to mid-20th century advertisements that included pregnant women smoking cigarettes and doctors promoting their favorite brand. Cigarettes were framed as the “healthy” choice, encouraging the weight conscious to choose a smoke over a sweet—and the public fell for it.

Subsequently, we were duped again with “light” and “ultra light” cigarettes, promising (but not delivering) significantly less harm to health and it remains to be seen how things will pan out for the newly introduced “reduced-nicotine cigarettes.”

With ECs, most of us aren’t sure what to think, but we know we won’t be fooled again. After all, as a recent review in the Journal of the American College of Cardiology put it, “Cardiovascular morbidity and mortality as a result of inhaled tobacco products continues to be a global health care crisis.” Given that, who in their right mind thinks we need a new way to deliver nicotine to the masses?¹

On the other hand, the same review notes that while the prevalence of smoking in the United States has fallen from 42% of adults in 1965 to 15% in September 2015, the people who continue smoking are likely to be seriously addicted and, often, with little interest or incentive in quitting. (As a recent headline put it: Smokers Want More Respect From Doctors.) Maybe it is time for a new approach.

Of course, important questions must be answered: What are the health effects of e-cigs? Might they be an opportunity to greatly impact smoking-related illness? Or are marketers just blowing smoke what and all these new devices really do is make it easy for new generations of smokers to move from vaping to puffing standard death sticks? (It’s hard to argue that these devices are not being targeted to kids given the thousands of EC flavors being sold, including chocolate, vanilla, cherry, cookies and cream, and bubble gum.)

The health effects of e-cigs remain a moving target and will require years more research, particularly into the long-term effects of EC use. Nevertheless, CardioSource WorldNews set out to gather the best information available on EC use and the health consequences of vaporizing a liquid that may contain nicotine along with other substances. Moreover, we did some limited field research to get a first-hand view of EC stores and were surprised at what we found (see In Search of e-Truth and Nothing but e-Truth).

R&B

The soul of the business of medicine these days seems to be in balancing risk and benefit. Even ardent supporters of electronic cigarettes usually do not support the use of these devices by non-smokers, no matter what their age. But the same way a cardiologist will prescribe a drug with known side effects to appropriately selected patients, ECs (as opposed to conventional tobacco smoking) might—if used properly—lower the risk of multiple diseases and chronic conditions, making the risk benefit analysis acceptable.

Also, let’s face it: drug effects are nearly universally confined to the people taking the drug. If you’re on pharmacotherapy, there is little chance of the person sitting next to you suffering second-hand exposure. The same can’t be said of conventional cigarettes; so, to the degree that vaping protects the non-smoking public, that alone is a beneficial effect.

Still, appropriate regulation and quality control become perplexing issues and all of this could go wrong in so many ways.

The U.S. Food and Drug Administration (FDA) and Health Canada have both looked at regulating electronic cigarettes and so far have reserved judgment, although an FDA decision is expected in the near future. Currently, the FDA regulates only ECs that are marketed for therapeutic purposes.

The United Kingdom, on the other hand, has been proactive in its approach to e-cigarettes and supportive of their use as a relatively safe means to stop or reduce smoking. Public Health England (PHE) released two reports in 2014 and an updated report just this August.² In the most recent report, PHE ignited a firestorm of criticism when it said that “using EC is around 95% safer than smoking.” (PHE is an operationally autonomous executive agency of the U.K. government’s Department of Health.)

Vaping: The New Gateway for Teens…

Is EC use leading to cigarette smoking among non-smokers, especially young people? That’s the $1.7 billion question; also known as the expected U.S. sales for e-cigs this year alone. Among American teenagers, cigarette smoking has dropped 64% from 1997 to 2013; however, according to a report in the October 16, 2015, Morbidity and Mortality Weekly Report, marijuana use doubled during the same time period. Overall, the U.S. Centers for Disease Control and Prevention (CDC) finds plenty of youngsters still light up: 30% of white, black, and Hispanic teens smoked cigarettes, cigars, or marijuana in 2013 alone.

E-cig numbers are a little harder to come by, but according to the CDC’s 2014 National Youth Tobacco Survey, e-cigarette use (use on at least 1 day in the past 30) has tripled among middle and high school students (Figure). There are now 2.5 million kids using e-cigarettes. Importantly, more than a quarter million youth who had never smoked a cigarette used ECs in 2013, according to another CDC analysis, reflecting—in this category alone—a three-fold increase, from about 79,000 in 2011 to more than 263,000 in 2013.

The most recent data mark a first: it is the first time since the CDC started collecting data on e-cigarette use in youth that current EC use has surpassed current use of every other tobacco product overall, including conventional cigarettes. Hookah smoking (which continues wafting through college towns throughout the United States) also roughly doubled for middle and high school students, while cigarette use declined among high schoolers and remained unchanged among those in middle school.

There is concern that ECs are a gateway device hooking a new generation on smoking, but these studies are small and methodologically limited. One such study was recently published in JAMA Pediatrics.³ In that study, Brian A. Primack, MD, PhD, and colleagues from the University of Pittsburgh School of Medicine, showed that among a group of teenagers who had tried ECs but who, based on their answers to a series of questions, were deemed to be “nonsusceptible” to cigarette smoking, EC use was independently associated with progression to smoking.

The study got a lot of press, but even the study’s first-author is not comfortable with the reporting. Dr. Primack told CSWN, “I definitely appreciate that this is an early finding and because our outcome was progression to any cigarette smoking, even just a puff, it doesn’t tell us whether they are more likely to progress to frequent, continuous, or lifelong smoking.” However, he added that his study “is an important milestone (but) we haven’t had time to follow people for years at this point because e-cigarette use is so new. This is the normal progression of how you study a question like this.”

It’s different in the U.K., where there don’t seem to be any trends at all. According to the latest statistics from Stop Smoking England, released in August 2015 and based on household surveys, EC use among nonsmokers is “negligible” and not apparently rising. Peter Hajek, PhD, gave a talk on this topic at the 2015 European Society of Cardiology (ESC) meeting and reported that while children do “experiment” with them, they don’t tend to progress to using them daily. Dr. Hajek is the director of the Wolfson Institute of Preventive Medicine’s Tobacco Dependence Research Unit at Queen Mary University of London and a co-author of the recent PHE report referenced above. (Also, he was first author of a recent major review on EC use and their potential for harm and benefit.⁴)

…Or Smoking Cessation Tools?

Do e-cigarettes really help smokers stop smoking? It depends who you ask. Among smokers, e-cigarettes have been embraced by many as a means to cut down or eliminate tobacco use. Indeed, there is some evidence that ECs are a better option than the traditional cessation aids. For example, a systematic review published in September 2015 concluded that e-cigarette use can reduce the number of cigarettes smoked and withdrawal symptoms.⁵ However, there is also evidence that they don’t lead to higher cessation rates compared to those who don’t use ECs.

A 2014 Cochrane Review addressed this question, finding only two randomized controlled trials on the topic, both of which used early e-cigarette devices that provide less nicotine than newer devices. The authors’ conclusions reflect the lack of clarity on this issue:

“There is evidence from two trials that ECs help smokers to stop smoking long-term compared with placebo ECs. However, the small number of trials, low event rates and wide confidence intervals around the estimates mean that our confidence in the result is rated ‘low’ by GRADE standards… No evidence emerged that short-term EC use is associated with health risk.”

Dr. Primack, the first author on the teen gateway study in JAMA Pediatrics, has experience with EC as smoking cessation tools in his family medicine practice. “There is this potential, theoretical benefit where if we could somehow magically get every smoker to convert to EC tomorrow, we would reduce disease by huge amounts, but this really hasn’t panned out in reality.”

His experience has been that EC users get very excited in the beginning, and may stop or reduce their tobacco use but, after the “honeymoon phase,” tend to revert back to smoking or at least dual use.

“What they’ve really done is found a way of sustaining their nicotine addiction in this society, and also it is sort of saying that nicotine addiction is really OK, which is a slippery slope.”

He doesn’t recommend e-cigs as a means for quitting smoking, but tries to support patients who come to him already using them and encourage them to drop their nicotine levels (in the e-liquid) to zero, if possible.

One unanswered question is whether better support for those trying to use EC to quit smoking might increase cessation rates.

In the U.K., the National Centre for Smoking Cessation and Training (NCSCT) has recommended “practitioners be open to EC use among smokers trying to quit, particularly if they have tried other methods of quitting and failed.” The group also offers detailed guidelines for smokers wanting to use ECs to quit, including differences in puffing on EC versus regular cigarettes, the need to try different types of ECs to find one that works for them, and that multi-sessional behavioral support is likely to improve their success of quitting.

The U.K.’s PHE report notes that ECs are very popular among those wishing to quit smoking, much more so than other cessation aids. They said, “It is not known whether current EC products are more or less effective than licensed stop-smoking medications, but they are much more popular, thereby providing an opportunity to expand the number of smokers stopping successfully. Some English stop-smoking services and practitioners support the use of EC in quit attempts and provide behavioral support for EC users trying to quit smoking; self-reported quit rates are at least comparable to other treatments. The evidence on ECs used alongside smoking on subsequent quitting of smoking is mixed.”

In the recent Smoking in England report, the authors found that ECs have helped approximately 20,000 smokers to stop in 2014 who would not have stopped otherwise. The American Heart Association released a policy statement on the topic at last year’s Annual Scientific Sessions, which was published in Circulation.⁶ In it they said:

“If a patient has failed initial treatment, has been intolerant to or refused to use conventional smoking cessation medication, and wishes to use e-cigarettes to aid quitting, it is reasonable to support the attempt. However, subjects should be informed that although e-cigarette aerosol is likely to be much less toxic than cigarette smoking, the products are unregulated, may contain low levels of toxic chemicals, and have not been proven as cessation devices.”

The authors stressed the need for more research and expressed concern about teen use, continued addiction to nicotine, and the renormalization of smoking.

Do You Know What You’re Vaping?

Indeed, one big issue with ECs is the lack of regulation and quality control surrounding the liquid or “smoke juice” used to make the vapor. E-cigarette liquid is made from essentially four ingredients: water, propylene glycol and/or vegetable glycerin, nicotine, and added flavors.

According to the U.S. Agency for Toxic Substances & Disease Registry, propylene glycol is a “synthetic liquid substance that absorbs water.” It is used to make polyester compounds and as a base for de-icing solutions. The FDA classifies it as an additive that is “generally recognized as safe” for use in food and it’s used to absorb extra water and maintain moisture in certain medicines, cosmetics, and food products (e.g., shredded coconut and frostings). It’s also used as a solvent for food colors and flavors that are insoluble in water. Hence its use in e-cigs as a stabilizer for the flavorings. Propylene glycol is not classified as a cancer-causing agent but the long-term effects of inhaling an aerosolized version are unknown.

Besides concern over propylene glycol, there is early evidence that the concentrations of some of the flavor chemicals in EC liquids might be a toxicological concern. For example, an estimated 69% of sweet flavored liquids contain diacetyl, which is used to produce a rich, buttery flavor. It was tied to a 2000 report in which eight former employees of the Gilster-Mary Lee popcorn plant developed “popcorn lung” (known more prosaically as bronchiolitis obliterans). As CSWN was going to press, the American College of Chest Physicians released a case study of a 60-year-old male who was hospitalized twice before his acute lung injury was tied to his EC use and high diacetyl content. This concurs with media material from the American Physiological Society indicating that EC vapor can damage lung cells even when the liquid being vaped is nicotine-free.

As for the nicotine, of course, it is a natural insecticide, but in small doses it acts as a stimulant in mammals. It is this stimulant effect that is thought to make nicotine so addictive. However, a look at nicotine delivery products that don’t employ combustion indicates that nicotine without smoking might be less evil.

“The problem is not nicotine,” said Jean-Francois Etter, PhD, in an interview with CSWN. “The problem is really combustion because if you look at the beginning of the 20th century, there weren’t so many people dying from lung cancer even though a lot of men used tobacco because until the end of the 19th century, tobacco wasn’t smoked; it was snorted or chewed.”

Dr. Etter is from the University of Geneva and has almost two decades of experience in conducting smoking etiology, prevention, and cessation research, plus he was among the first to publish on electronic cigarettes. It is true that the problem with smoking is not just the nicotine: when tobacco is burned, a complex chemical mixture of more than 7,000 compounds is produced, many of which are causally associated with premature deaths and diseases affecting nearly every organ system in the body. Many of the concerns regarding nicotine relate to the ability of nicotine to release catecholamines, including hemodynamic effects, such as adverse effects on lipids, endothelial dysfunction, and insulin resistance.

Still, nicotine gum and nicotine patches, both of which have been around for more than 30 years and studied extensively, appear to be relatively safe even in long-term users, said Dr. Etter. Getting hooked on these nicotine-delivery products is not common, although in the case of the gum, it can happen, but he wouldn’t call it “addiction.”

“In order to use the term addiction you need to have two components—the compulsion to use the substance, and the negative social effect,” said Dr. Etter. “In the case of nicotine gum you can argue that some people might feel the compulsion to use nicotine gum, but there are no bad health or social effects except for the money that they spend.”

Nicotine does increase blood pressure and heart rate, but again, using the gum and patch as examples, it doesn’t seem to have adverse cardiovascular effects, even in individuals with cardiovascular disease, said Dr. Etter, although the jury is still out on this. Dr. Hajek agreed. Nicotine does have adverse effects in pregnancy, but it seems to have “no contribution to lung disease, cancer, or as far as we know even heart disease, although there are some grey areas in that still.”

You Snus, You Lose? Maybe Not

Dr. Hajek added that long-term users of Scandinavian snus, a form of “spitless” chewing tobacco that is placed under the upper lip for extended periods of time, don’t show an increase in cancer risk, including mouth cancer, although there is some indication that it may increase the risk of pancreatic cancer.

Interestingly, respiratory cancer rates in Sweden, where snus remained legal after being banned in 1992 in the rest of the European Union, are the lowest in all of Europe. Sweden also has steadily declining smoking rates albeit with steadily increasing numbers of snus users who are less likely to become a daily smoker.

In that previously mentioned JACC review on smoking and EC use, the authors noted that while snus use was not associated with increased risk of myocardial infarction (MI), in a pooled analysis of observational data, evidence does suggest that quitting snus after an MI nearly halved mortality risk.⁸

Research on the direct cardiovascular effects of ECs is limited, but several abstracts have been presented at ESC meetings in the past few years, all done by a group of researchers at the Onassis Cardiac Surgery Center in Athens, Greece. They found that while arterial elasticity and left ventricular function are both acutely impaired after smoking tobacco, no immediate adverse effect on either is observed after EC use. Also, the significant elevations in coronary circulation and carboxyhemoglobin levels seen after smoking were not noted after vaping.

Puff, the Magic Draggin’ Machine

Advocates and opponents both acknowledge insufficient data on the amount of hazardous compounds emitted from e-cigarettes and the long-term effects of repeatedly inhaling them deep into the lungs. However, while awaiting long-term data, there are some strong hints that EC vapor is probably not perfectly healthy but, not surprisingly, maybe not as bad as the popular press would have us believe.

In January 2015, a research letter published in The New England Journal was entitled “Hidden formaldehyde in E-cigarette aerosols.”⁹ In this short piece, researchers from Portland State University, OR, reported that a third-generation EC (with variable power settings), when set to maximum power and a long puff duration, generated levels of formaldehyde that could be five times or more than the exposure of a pack-a-day tobacco cigarette smoker. To be clear, their “users” were puff machines, not people.

The press coverage was extensive and went both ways; advocates blasted others for sowing confusion and fear; critics argued they had science on their side. Maybe. Maybe not.

A closer look at the technical details showed that only under extreme circumstances could an EC produce these super high levels of formaldehyde, use that is colloquially called a “dry puff.” This term refers to an unpleasant burning taste caused by an insufficient supply of liquid so that the evaporation rate is higher than liquid supply. Users apparently learn to avoid this phenomenon because it tastes terrible.

Konstantinos Farsalinos, MD, from the Onassis Cardiac Surgery Center in Athens, has been vocal in arguing that the conditions referred to in the New England Journal of Medicine letter were based on unrealistic use, saying, “Taste prevents e-cigarette users from exposing themselves to excessive formaldehyde from overheating of the coil.” His group went further, publishing a study in the journal Addiction in August 2015, confirming that experienced users could overheat the liquid which was associated with aldehyde formation, but only with extreme use conditions, which smokers will readily find unpleasant and will likely “detect and avoid.”¹⁰

In a press statement, Dr. Farsalinos said: “Minimal amounts of aldehydes are released in normal vaping conditions, even if high power levels are used. In those normal-use conditions, aldehyde emissions are far lower than in tobacco cigarette smoke.”

The researchers also requested the original letter be retracted, a request that was denied because, as New England Journal of Medicine executive editor and online editor Edward W. Campion, MD, said to the website Retraction Watch, there was “no evidence of scientific misconduct, and we see no grounds for retraction. Disagreements about interpretation of data are not grounds for retraction.”

David H. Peyton, PhD, professor of chemistry at Portland State University and an author of the original NEJM letter, told Retraction Watch: “No one seems to be arguing with the science; they just seem very much to want the shading of the interpretation to match certain agendas.”

For their part, the Public Health England report writers concluded that “normal vaping generated negligible aldehyde levels” and that “although e-liquid can be heated to a temperature which leads to a release of aldehydes, the resulting aerosol is aversive to vapers and so poses no health risk.”

Even proponents of e-cigarettes suggest that appropriate regulation of liquid manufacturing is needed. When asked how he would like to see EC regulated, Dr. Etter replied that the key word is “proportionate.”

“I would like reasonable regulations covering advertising of these devices and covering the content of the liquids and the temperatures and what is producing the vapors. But the key word is proportionate. Reasonable and proportionate regulations.”

For his part, Dr. Hajek reported in his ESC talk that “some impurities and potential toxicants” have been found in EC liquids, but added, “The dose makes the poison,” and that the studies done so far don’t convey much useful information as they don’t show clearly adverse impact on health based on real-world use.

The “Renormalization” of Smoking?

One big concern regarding a new generation of nicotine users is that e-cigs might “renormalize” smoking behavior, said Dr. Primack.

For his part, Dr. Hajek calls the lumping of EC with tobacco cigarettes a category error. “You have to digest the information… that it doesn’t contain that many risks and see that we are comparing a tiger with a kitten.” He also rejects any effort to discredit ECs by attacking nicotine use.

“I think they don’t appreciate that using nicotine without health risks is very much like drinking coffee. It’s a mild stimulant with no serious health effects we know of, but they see nicotine use as somehow morally wrong by itself.”

In an interview with CSWN, Pamela B. Morris, MD, FACC, from the Medical University of South Carolina (Charleston) and first author of the JACC review on the cardiovascular effects of smoking and electronic cigarettes noted that rates of smoking cessation have declined in recent years.¹ “Although the prevalence has decreased globally, because of the increase in the population, we have increasing numbers of smokers.” Specifically, from 1980 to 2012, the number of smokers in the world has increased from approximately 721 million to 967 million. She suggested that those who continue to smoke have “a high residual addiction” but also that “messaging fatigue” has set in, limiting smoking cessation efforts.

With EC, said Dr. Morris, the highly addictive act of smoking remains an issue, even if the substance itself is less toxic. “We do not know enough about the health consequences of electronic cigarettes,” she said, but “if they prove to be a gateway delivery system, we need to be very proactive in reducing the uptake of use.”

References:

1. Morris PB, Ference BA, Jahangir E, et al. J Am Coll Cardiol. 2015;66:1378-91.
2. McNeill A, Brose LS, Calder R, et al. Public Health England, August 2015. gov.uk/government/publications/e-cigarettes-an-evidence-update (accessed October 18, 2015).
3. Primack BA, Soneji S, Stoolmiller M, et al. JAMA Pediatr. 2015 Sep 8:1-7. [Epub ahead of print]
4. Hajek P, Etter J-F, Benowitz N, et al. Addiction. 2014;109:1801-10.
5. Gualano MR, Passi S, Bert F, et al. J Public Health (Oxf). 2015;37:488-97.
6. Bhatnagar A, Whitsel LP, Ribisl KM, et al. Circulation. 2014;130:1418-36.
7. Varlet V, Farsalinos K, Augsburger M, et al. Int J Environ Res Public Health. 2015;12:4796-815.
8. Arefalk G, Hambraeus K, Lind L, et al. Circulation. 2014;130:325-32.
9. Jensen RP, Luo W, Pankow JF, et al. N Engl J Med. 2015;372:392-4.
10. Farsalinos KE, Voudris V, Poulas K. Addiction. 2015;110:1352-6.

Keywords: CardioSource WorldNews, Electronic Nicotine Delivery Systems, Global Health, Nicotine, Smoke, Smoking, Tobacco Use Cessation Devices, Smoking Cessation, Tobacco Use Disorder

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