The emerging phenomenon of electronic cigarettes

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The status quo in smoking cessation presents smokers with just two unpleasant alternatives: quit or suffer from the harmful consequences of continuing to smoke. However, there is a third choice for smokers: switching to the electronic cigarette. The electronic cigarette is a cigarette-shaped electronic product, manu factured and marketed by several different companies, pow-ered by a lithium-ion rechargeable battery that is designed to vaporize nicotine to be inhaled (Figure 1) [101]. Although the early concept appeared in a patent acquired by Herbert A Gilbert in 1963, the modern electronic cigarette was invented by Chinese pharmacist Hon Lik in 2003 and introduced to the market the follow-ing year [201]. In 2004, the Chinese company Ruyan® (Hong Kong, China) introduced and marketed for the first time an electronic device capable of emulating cigarette smoking: the elec-tronic cigarette was born. Within a few years the electronic cigarette market had greatly expanded and, besides Ruyan, several other companies began to introduce similar products. Currently, the electronic cigarette is continuously evolving, with new and improved models making it to the market at a yearly rate. Sufficient regulation of the electronic cigarette is currently lacking, but the WHO Study Group on Tobacco Product Regulation classifies electronic cigarettes as electronic nicotine delivery systems [1].

Besides vaporizing nicotine to be inhaled, elec-tronic cigarettes may also provide a coping mech-anism for conditioned smoking cues by replacing some of the rituals associated with smoking ges-tures (e.g., the hand-to-mouth action of smok-ing), and for these reasons it is now perceived by users as a potentially more attractive substitute for smoking than low toxin smokeless tobacco [202]. Given that neither tobacco nor combustion are necessary for its operation, it is likely that this product could be used as a lower-risk substitute for tobacco cigarettes. In addition, people report buying them to help quit smoking, to reduce cigarette consumption, to relieve tobacco with-drawal symptoms due to workplace smoking restrictions and to continue to have a ‘smoking’ experience but with reduced health risks [2]. The electronic cigarette is an emerging phenomenon that has become increasingly popular in the past few years [3], with groups of users (who call themselves ‘vapers’ because they inhale vapor, not smoke) who formed an active community (both online and in person) to strongly advo-cate for these products [4]. Contrary to all other smoking cessation products, the electronic ciga-rette has created a social phenomenon of global proportion, which calls for research, legislation and product development.

The focus of this article is the health effects of using an electronic cigarette, with consideration

Pasquale Caponnetto1,2, Davide Campagna1,2, Gabriella Papale1,2, Cristina Russo1,2 and Riccardo Polosa*1,2

1Centro per la Prevenzione e Cura del Tabagismo (CPCT), Azienda Ospedaliero-Universitaria ‘Policlinico-Vittorio Emanuele’, Università di Catania, Catania, Italy 2Institute of Internal Medicine, S. Marta Hospital, Azienda Ospedaliero-Universitaria ‘Policlinico-Vittorio Emanuele’, Università di Catania, Catania, Italy *Author for correspondence: [email protected]

The need for novel and more effective approaches to tobacco control is unquestionable. The electronic cigarette is a battery-powered electronic nicotine delivery system that looks very similar to a conventional cigarette and is capable of emulating smoking, but without the combustion products accountable for smoking’s damaging effects. Smokers who decide to switch to electronic cigarettes instead of continuing to smoke would achieve large health gains. The electronic cigarette is an emerging phenomenon that is becoming increasingly popular with smokers worldwide. Users report buying them to help quit smoking, to reduce cigarette consumption, to relieve tobacco withdrawal symptoms due to workplace smoking restrictions and to continue to have a ‘smoking’ experience but with reduced health risks. The focus of the present article is the health effects of using electronic cigarettes, with consideration given to the acceptability, safety and effectiveness of this product to serve as a long-term substitute for smoking or as a tool for smoking cessation.

Keywords: cigarettes • electronic cigarettes • nicotine addiction • smoking • smoking cessation

The emerging phenomenon of electronic cigarettesExpert Rev. Respir. Med. 6(1), 63–74 (2012)

Expert Rev. Respir. Med. 6(1), (2012)64

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given to the acceptability, safety and effectiveness of this product to serve as a long-term substitute for smoking or as a tool for smoking cessation.

The subjective experience of using the electronic cigaretteThe electronic cigarette is designed for the purpose of providing a flavor and physical sensation similar to that of inhaled tobacco smoke, while no smoke or combustion is actually involved in its operation. When a user sucks on the device, an electronic sensor detects air flow and automatically activates the heating element that heats the liquid in the cartridge so that it is vapor-ized. Upon inhalation, the same electronic sensor lights up a red LED indicator to signal activation of the device with each puff. Most replaceable cartridges contain nicotine suspended in propylene glycol (PG), glycerol and water, but they can also contain flavorings (e.g., fruit or mint). There are also cartridges containing no nicotine, created for those individuals who want to reproduce smoking habits without the use of nicotine. The heating element that vaporizes the liquid in the cartridge and generates the mist with each puff is the atomizer. This is powered by a lithium-ion rechargeable battery that is housed in the body of the electronic cigarette. The generated mist delivers nicotine into the bloodstream. The data from human laboratory studies are limited, but suggest that electronic cigarette use is unlikely to yield a high concentration of nicotine in the circulation of inexperienced users [5,6]. However, experienced users can extract

as much nicotine from electronic cigarettes as smokers can from tobacco cigarettes [7].

Electronic cigarettes look very similar to the conventional ciga-rette and are capable of emulating cigarette smoking, but there are differences. Probably the most immediate difference between the conventional cigarette and the electronic cigarette is tactile. The conventional cigarette is soft and light, whereas the electronic cig-arette is hard, cold and a bit heavy. Hence, handling an electronic cigarette feels very different from a conventional cigarette. The smell and taste of the tobacco cigarette are characteristics diffi-cult to reproduce. However, some nicotinized electronic cigarette cartridges may replicate the flavor of tobacco. The whole puffing experience is different and requires some degree of adaptation from smoking to vaping. Generally speaking, most electronic cigarettes require stronger suction to smoke than conventional cigarettes [8]. Also, the amount of aerosol produced by electronic cigarettes decreases with vaping, which requires increasing puff strength to produce the same amount of aerosol. It may take some time to master a satisfying technique. Thus, several caveats appear to limit the widespread adoption of electronic cigarettes by smok-ers, and it is important to assess the current level of satisfaction of users with these products.

Specifically designed surveys may be useful to identify the unmet needs of the typical electronic cigarette consumer. In a recent survey of users, 81 respondents reported more positive than negative effects with electronic cigarettes: many reported posi-tive effects on the respiratory system (improved breathing and

LED lightsup when the smokerdraws on the cigarette

controls heater and light

detects when smokertakes a drag

aspiration

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vaprorizes liquid andnicotine

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holds nicotine dissolvedin propylene glycol

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Figure 1. Structure of the electronic cigarette. The electronic cigarette is a battery-powered electronic nicotine-delivery device resembling a cigarette designed for the purpose of providing inhaled doses of nicotine by way of a vaporized solution to the respiratory system. This device provides a flavor and physical sensation similar to that of inhaled tobacco smoke, while no smoke or combustion is actually involved in its operation. It is composed of the following key components: the inhaler, also known as the ‘cartridge’ (a disposable plastic mouthpiece, resembling a tobacco cigarette’s filter, containing an absorbent material saturated with a liquid solution of propylene glycol and vegetable glycerin in which nicotine may be dissolved); the atomizing device (the heating element that vaporizes the liquid in the mouthpiece and generates the mist with each puff); and the battery component (the body of the device – resembling a tobacco cigarette – which houses a lithium-ion rechargeable battery to power the atomizer). The body of the device also houses an electronic airflow sensor to automatically activate the heating element upon inhalation and to light up a red LED indicator to signal activation of the device with each puff. The LED indicator also signals low battery charge.

Caponnetto, Campagna, Papale, Russo & Polosa

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reduced cough and expectoration), which were probably associ-ated with stopping smoking [9]. The fact that electronic cigarettes do not produce any unpleasant odors and are unlikely to generate environmental tobacco smoke was also appreciated. Most impor-tantly, many respondents reported that the electronic cigarette helped them quit smoking, and several compared it favorably with either a nicotine patch or bupropion. Interestingly, dry mouth and throat was a frequent adverse effect of the electronic cigarette. Many respondents complained of the poor quality of electronic cigarettes, their frequent failures, the lack of durabil-ity of cartridges and batteries and, ocasionally, the liquid leaking from the product during usage. Although users’ comments were generally positive, many were concerned about the safety and toxicity of electronic cigarettes, and questioned why no study has yet investigated these aspects. Several respondents were also concerned about the future legal status of electronic cigarettes and that they could be banned. In a second much larger survey of users, 3587 participants reported that they use electronic ciga-rettes as an aid to quit smoking, to avoid relapse and to deal with withdrawal symptoms, similar to individuals who use nicotine replacement therapy [10]. Many participants used them because they were perceived to be less toxic and cheaper than tobacco. Users of nicotine-containing electronic cigarettes reported only slightly superior effects on withdrawal than users of non-nicotine electronic cigarettes, suggesting that nicotine delivery explains only part of the effect of these devices on withdrawal, and that the sensory and behavioral components of the electronic cigarette are also important. Action on Smoking and Health UK surveyed 1380 smokers, of whom 486 had used electronic cigarettes [11]. In the national survey, 9% of smokers had tried them and 3% were still using them. In a focus group, those who had not tried elec-tronic cigarettes pictured a device that looks and performs much like a real cigarette. Those who had tried electronic cigarettes put greater importance on an ‘authentic smoking experience’ and strength of nicotine [11]. These data demonstrate a widespread interest among smokers, particularly heavy smokers, for alterna-tives to smoking and highlight a variety of factors limiting the acceptability of products currently available.

In a recent prospective proof-of-concept study, we monitored possible modifications in smoking habits and product preference of 40 smokers (not willing to quit) experimenting a commercially available brand of electronic cigarette (Categoria™ electronic cigarette; Arbi Group Srl, Milan, Italy) with a 7.4 mg nicotine cartridge [12]. The electronic cigarette under study achieved high scores for satisfaction and for helpfulness (enabling individuals to refrain from smoking). Moreover, it was highly likely that par-ticipants would recommend it to friends or relatives who wanted to stop/reduce smoking. Although the overall participants’ per-ception and acceptance of the product was good (most positive features included pleasure of inhalation and exhalation of the vapor, cleaner and fresher breath, and an absence of odors in clothing and hair), its ease of use could be improved and techni-cal defects reduced. During the course of the study, five study participants could not use the product as recommended and had to be retrained within 72 h. Three participants reported that the

device often failed to produce mist when puffed (three atomizers had to be substituted). Another two were given a faulty charger (chargers were immediately replaced). According to study par-ticipants, the perception and acceptance of the product could be improved by increasing manufacturing standards, by providing a recharge lasting at least 24 h, by reducing the weight of the device and by substituting the hard plastic mouthpiece. The latter two suggestions in particular would improve device acceptability for some common rituals of cigarette smoking (e.g., keeping the cigarette between lips).

Earlier electronic cigarettes models are hampered by inadequate manufacturing standards with leaky cartridges, an inadequate amount of vapor or nicotine and batteries lasting only a few hours. Manufacturers are doing their job in correcting design flaws in the hardware and have moved on to models with batteries that last 24 h, cartridges that do not leak, cartridges that do not contain filler material, models that produce a higher volume of visible vapor (many users consider this important) and stronger nicotine levels. Further improvements are in progress to improve users’ satisfaction with the product.

Electronic cigarettes: what about the safety concerns?The electronic cigarette concept is currently contested by several health groups, either for pragmatic reasons or because they are opposed to any recreational use of nicotine. One of the main arguments used by this group is that electronic cigarettes may be dangerous.

Detailed toxicology characterization of the components con-tained in electronic cigarettes’ liquid and vapor using gas chro-matography mass spectrometry is accumulating rapidly and dem-onstrates that their primary components are water, PG, glycerin and nicotine [203]. PG has undergone extensive testing and is widely used in a variety of consumer products, including food. It is also approved by US FDA for a variety of pharmaceutical formulations [204].

In an independent study, Laugesen tested electronic cigarette mist for over 50 priority-listed cigarette smoke toxicants and found none [205]. This report only revealed traces (8.2 ng/g) of tobacco-specific nitrosamines (TSNAs) in the ‘high’ nicotine cartridge of a Ruyan brand electronic cigarette. However, it must be noted that this amount is equal to the quantity reported to be present in a nicotine medicinal patch. Likewise, labora-tory analyses carried out by the FDA failed to find carcinogens and toxic chemicals in most of the products tested with a single exception: traces (~1%) of diethylene glycol were detected in the liquid of one of the 18 samples, but this represents a nontoxic quantity [206]. The FDA analyses could not detect any harmful chemical in the vapor. Moreover, an independent analysis of the same electronic cigarette products tested by the FDA found no evidence of carcino genic TSNAs in their aerosol [207]. Recently, Cahn and Siegel have reviewed the evidence regarding the safety of the liquid in electronic cigarettes [13]. TSNAs were reported in two studies, but at trace levels, which are similar to those found in a nicotine patch, and, most importantly, approximately 500–1400-fold lower than TSNA levels measured in regular

The emerging phenomenon of electronic cigarettes


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cigarettes (electronic cigarettes contain only 0.07–0.2% of the TSNAs present in tobacco cigarettes) (Table 1). This is not sur-prising. Electronic cigarettes deliver a nicotine vapor without the combustion products that are responsible for nearly all of smoking’s damaging effects. Temperatures of up to 950°C are generated with each puff of a lit cigarette and some 5000 or so chemicals, many of which are toxic or carcinogenic, are gener-ated during the combustion process [14]. By contrast, electronic cigarettes use the process of vaporization rather than combustion and the low operating temperature of the atomizer (~50–60°C; ~5–10% of the temperature of a lit cigarette) suggests that electro-nic cigarettes, as a class, are unlikely to emit cigarette toxicants in their mist [205].

Japanese researchers conducted a safety assessment of electronic cigarettes that included 32 smokers and found no abnormal changes in blood pressure, hematological data or blood chemistry and no severe adverse events after 4 weeks of regular use [15]. Our recent clinical safety assessment of one product in 40 smokers showed that mouth and throat irritation and dry cough were com-monly reported in the initial few weeks of use, but all appeared to wane spontaneously by the end of the study, after 24 weeks of regular use (Figure 2) [12]. These are likely to be secondary to exposure to PG mist generated by the electronic cigarettes’s atom-izer. PG is a low-toxicity compound widely used as a food addi-tive and in pharmaceutical preparations [204]. Exposure to PG mist may occur from smoke generators in nightclubs, theaters and aviation emergency training, and is known to cause ocular, mouth, throat and upper airway irritation, and cough [16,17]. In all these cases, PG has to be heated in order to generate fog or mist. In our recent study, we have shown that some mouth irritation, throat irritation and dry cough could result from the exposure to PG mist generated by the electronic cigarette’s atomizer [12]. However, these symptoms were minor and wane spontaneously with time (Figure 2).

Dizziness was often reported by participants at the beginning of the study and can be brought about by the hyperventilation

associated with the increased puffing time with the electronic cigarette. The substantial reduction in the frequency of dizziness observed by the end of the study may be due to the improved familiarization with the puffing technique. Interestingly, typical withdrawal symptoms were not reported during the course of the study. It is possible that the electronic cigarette, by providing a coping mechanism for conditioned smoking cues, could mitigate withdrawal symptoms associated with smoking reduction and smoking abstinence, as shown for nicotine-free inhalators [18]. In addition, smoking reduction with the brand under investigation led to a substantial decrease in exhaled carbon monoxide levels [12].

The evidence noted above suggests that electronic cigarettes do not raise serious health concerns and can be seen as a safe way to smoke. Moreover, retailers all over the world have already sold millions of electronic cigarettes, yet there is no evidence that these products have endangered anyone, and no indication that electronic cigarettes are any more of an immediate threat to public health and safety than traditional cigarettes, which are readily available to the public (Figure 3). Although the current data are insufficient to conclude that electronic cigarettes are safe in abso-lute terms and larger and longer studies are needed to comprehen-sively assess their safety (particularly in relation to their long-term use), these products appear to be much safer than tobacco ciga-rettes and comparable in toxicity to conventional nicotine-replace-ment products. However, it is important to adequately regulate these products so that the safety of consumers is safeguarded.

Detractors of the electronic cigarette concept also claim that nicotine is harmful. This has generated great confusion and fierce debate. Nicotine fulfils all the criteria of an addictive agent, including psychoactive effects, drug-reinforced behav-ior, compulsive use, relapse after abstinence, physical depen-dence and tolerance. Nicotine stimulates specialized receptors in the brain that produce both euphoric and sedative effects [19]. Individuals who have emotional dysfunctions or attention deficits are more likely to start smoking and less likely to be able to quit. Nicotine has beneficial effects on attention, con-

centration and mood. These smokers may be depending on nicotine as a means of self-medication [20].

Are there important associated adverse health consequences of nicotine intake? Without doubt, nicotine medication is much safer than cigarette smoking, with the latter delivering not only equal or increased levels of nicotine, but also thou-sands of toxic combustion products to the smoker. However, there are some concerns involving the safety of long-term exposure to nicotine, including cardiovascular dis-ease, cancer and reproductive disorders [21]. Nicotine is a sympathomimetic drug that releases catecholamines, increases heart rate and cardiac contractility, constricts cutane-ous and coronary blood vessels and tran-siently increases blood pressure. Nicotine

Table 1. Summary data of maximum tabacco-specific nitrosamine levels in various cigarettes and nicotine-delivery products, including electronic cigarettes†.

Product NNN NNK NAT NAB

Nicorette® gum (4 mg) 2.00 ND ND ND

NicoDerm® CQ® patch (4 mg) ND 8.00 ND ND

Electronic cigarettes 3.87 1.46 2.16 0.69

Swedish snus 980.00 180.00 790.00 60.00

Winston (full) 2200.00 580.00 560.00 25.00

Marlboro (full) 2900.00 960.00 2300.00 100.00

Camel (full) 2500.00 900.00 1700.00 91.00

Marlboro (ultra-light) 2900.00 750.00 1100.00 58.00†ng/g, except for nicotine gum and patch, which are ng/gum piece and ng/patch.NAB: N’-nitrosoanabasine; NAT: N’-nitrosoanatabine; ND: Not detected; NNK: N’-nitrosonornicotine; NNN: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Adapted from [13].



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also reduces sensitivity to insulin and may aggravate or precipitate diabetes, and may also contribute to endothelial dysfunction. These various effects of nicotine on the cardiovascular system could, in theory, promote atherogenesis and precipitate acute isch-emic events in people who have coronary artery disease. This has been of particular concern in smokers who use nicotine medi-cation while they are still smoking. However, increased cardio-vascular risk due to nicotine medication does not appear to be a problem [21]. Nicotine is not a direct carcinogen, but there are concerns that it may be a tumor promoter. Whether nicotine is a cancer promoter in humans has not been established [21]. Suspected adverse reproductive effects of nicotine include, most prominently, fetal neuroteratogenic effects. In general, it is not desirable to use nicotine during pregnancy, but if the alternative is cigarette smoking, then nicotine medication is undoubtedly less hazardous [21]. Nicotine-replacement therapy used in the long term is well-tolerated without evidence of serious adverse health effects [22]. In conclusion, nicotine per se causes minimal risk when separated from inhaling smoke.

Electronic cigarettes: what about the clinical evidence?The electronic cigarette is a very hot topic that has generated considerable global debate, with some authorities wanting to ban

it or, at least, regulate it. Consequently, a formal demonstration supporting the efficacy and safety of these devices in clinical trials is of the utmost importance.

One of the earliest clinical trials of electronic cigarettes was conducted at the University of Auckland (New Zealand). Forty adult smokers of ten or more cigarettes per day were randomized to use an electronic cigarette containing 16 mg of nicotine or 0 mg of nicotine (placebo), a Nicorette® (McNeil Healthcare Ltd, Wokingham, UK) nicotine inhalator or their own brand cigarette. The 16-mg electronic cigarette alleviated the desire to smoke after overnight abstinence, was well tolerated and exhib-ited a pharmacokinetic profile more similar to the Nicorette inhalator than a tobacco cigarette [6]. A US study of 32 smok-ers comparing two brands of electronic cigarettes to the par-ticipants’ own brand found that ten puffs from either brand delivered little to no nicotine compared with ten puffs from the regular brand. However, both models effectively suppressed nicotine-withdrawal symptoms [23]. Canadian researchers exam-ined the reinforcing effects of electronic cigarettes with and without nicotine on 11 volunteers. Participants reported a reduc-tion in craving, regardless of the nicotine content [24]. The fact that the observed beneficial effects on craving and withdrawal symptoms appear to be independent of the nicotine content in

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Figure 2. Adverse events reported by electronic cigarette users who completed all study visits. This illustration was developed based on the findings of the study by Polosa et al. [12].



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the electronic cigarettes requires explanation. The well-known powerful interaction between physical and behavioral depen-dence of smoking [25,26] suggests that the reported positive effects of the electronic cigarette may also be owing to its capacity to provide a coping mechanism for conditioned smoking cues by replacing some of the rituals associated with smoking gestures for some smokers (e.g., the hand-to-mouth action of smoking), even if little or no nicotine is present. In agreement with this, we have recently demonstrated that nicotine-free inhalators can only improve quiting rates in those smokers for whom handling and manipulation of their cigarette played an important role in their ritual of smoking [18].

In two recent case series, we have reported objective measures of long-term smoking abstinence in challenging smokers with severe nicotine dependence and/or major depression who have quit after taking up an electronic cigarette [27,28]. This is quite outstand-ing when considering the fact that this result was accomplished

without the support of recommended nicotine-dependence treat-ments and smoking-cessation counseling, and with individuals who had repeatedly failed in previous attempts when provided with professional smoking-cessation assistance.

In our recent prospective 6-month proof-of-concept study, important modifications in smoking habits were reported in 40 smokers (not currently attempting to quit smoking or wish-ing to do so in the next 30 days) after using a commercial brand of electronic cigarette (Categoria electronic cigarette) loaded with a 7.4-mg nicotine cartridge [12]. Study participants were invited to attend a total of five study visits. During the first baseline visit, basic demographic and a detailed smoking his-tory were taken. Additionally, levels of carbon monoxide in exhaled breath were measured. Participants were then given a free electronic cigarette kit containing two rechargeable batteries, a charger and two atomizers, and instructed on how to charge, activate and use the electronic cigarette. A free supply of 7.4-mg

Addiction, stroke, Alzheimer’s diseaseAddiction

Electronic cigarette contains: Traditional cigarette contains:

Cataracts

Oral cancer, periodontitis

Atherosclerosis

COPD, lung cancer, pneumonia

Atherosclerotic heart disease,myocardial infarction

Pancreatic cancer

Aortic aneurysm

Renal cancer

Colon cancer, Crohn’s disease

Psoriasis

Infertility, miscarriage, low birthweight, cervial cancer

Bladder cancer

Myeloid leukemia, osteoporosis

Peptic ulcer disease, stomach cancer

Propylene glycol, glycerin, nicotine and food flavoring Nicotine, benzene, formaldehyde, lead, tar, methanol,hydrogen cyanide, butane, ammonia, chloroform,carbon monoxide, acetone, nitrosamines, aluminum,carbon dioxide, cadmium, arsenic, ethanol, vinyl chloride,radon, +3500 more chemicals and +50 known carcinogens

Figure 3. Medical infograph. The infograph was developed by the Consumer Advocates for Smoke-free Alternatives Association to provide medical service providers with a comparison of the potential health risks of cigarette smoke with the health risks of vapor. Since electronic cigarette liquid contains only propylene glycol, vegetable glycerin, flavorings and nicotine, the resulting vapor is unlikely to present any more disease risk than medicinal nicotine products – the risk of nicotine addiction. The many more toxic and carcinogenic ingredients in tobacco smoke are linked to numerous health problems. COPD: Chronic obstructive pulmonary disease. Adapted with permission from the Consumer Advocates for Smoke-free Alternatives Association (CASAA).



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nicotine cartridges (‘original’ cartridges; Arbi Group Srl) was also provided throughout the study and participants were trained on how to load them onto the electronic cigarette’s atomizer. Participants were invited to use it whenever they wanted and to attend four follow-up visits at weeks 4, 8, 12 and 24. At these visits we recorded their exhaled carbon monoxide levels and col-lected completed study diaries and unused study products. In this pilot study, we have shown for the first time that substantial and objective modifications in the smoking habits may occur in smokers using electronic cigarettes, with significant smoking reduction and smoking abstinence, and no apparent increase in withdrawal symptoms. Participants were not only enthusiastic about using the electronic cigarettes, but the majority (67.5%) were also able to adhere to the program and to return for the final follow-up visit at week 24, with an overall quit rate of 22.5% (Figure 4). Moreover, at least a 50% reduction in cigarette smok-ing was observed in 32.5% of participants. Overall, combined reduction and smoking abstinence was shown in 22 out of 40 (55%) participants, with an overall 88% fall in the number of cigarettes smoked per day. It is, however, possible that technical problems (particularly the product failures that went unreported) and difficulty of use (it takes time to familiarize with the puffing technique) could have had a negative influence on the total num-ber lost to follow-up and smoking cessation/reduction failures, and that a more positive outcome would be obtainable with the new improved models. Conversely, the ‘novelty’ effect of this new product could explain its widespread adoption, with many smokers willing to show off their new gadget in front of their fellow smokers and to the public.

The findings of this study are of great significance in view of the fact that all smokers in the study were, by inclusion criteria, not interested in quitting. Although not directly comparable with classic cessation and/or reduction studies with other pharma-ceutical products because of its design (the present study is not an ordinary cessation study and the study population included smokers not willing to quit), the results of our study are in general accordance with the findings published in the medical literature [29]. The fact that a substantial number of smokers unwilling to quit eventually switched to the electronic cigarette or quit alto-gether requires explanation. It is possible that for some partici-pants, satisfaction from electronic cigarette use was good enough to compensate for their need of own brand cigarette. This by itself can explain the behavior change in the nine participants (22.5%) who were not smoking at week 24. The replacement of the ritual of smoking gestures, the opportunity to reduce a bad smell, to reduce cost of buying traditional cigarettes and the perception of an improved general sense of wellbeing might have been responsible for their switching/quitting.

Although the data presented here are encouraging, large and carefully conducted prospective, randomized controlled trials will be required before a definite answer about the efficacy of these products can be formulated. Some of these trials are already in progress in Italy [208–210] and New Zealand [211], and hopefully they will be able to confirm and expand the positive preliminary clinical experience with these products.

Electronic cigarettes: potential for smoking cessationCurrent smoking cessation interventions can increase the chance of quitting in committed smokers who are already motivated and prepared to stop smoking [30], but a broader range of interventions are needed in order to bring more smokers into treatment and increase the numbers who are motivated to make quit attempts. Although not formally regulated as a pharmaceutical product, the positive preliminary clinical experience with these products could be confirmed and expanded in classic smoking-cessation trials of smokers motivated to quit.

The most common smoking-cessation method is nicotine replace-ment, which aims to address nicotine dependence [31]. Its primary mechanism of action is to partially replace the nicotine formerly obtained from tobacco smoking, aiding smoking cessation by atten-uating the reinforcing effects of nicotine delivered via tobacco, and therefore reducing the severity of withdrawal symptoms and crav-ings [32]. Approved nicotine replacement therapies do not completely control all symptoms of withdrawal because the available deliv-ery systems do not reproduce the rapid and high levels of nicotine achieved through tobacco use [33,34]. Differences in formulations (nicotine lozenge, gum, patch, nasal spray and inhaler) could have a distinct impact upon either withdrawal symptoms or urges to smoke, but there is little direct evidence that one nicotine product is more effective than another, perhaps with the only exception being the nicotine nasal spray [35]. It is possible that the electronic cigarette may deliver aerosolized nicotine in a more efficient manner.

Moreover, efficacy with nicotine-replacement therapies, as for all antismoking medications, is modest because it addresses only the physical component of smoking (i.e., nicotine addiction), and is unlikely to resolve the psychological components (cognitive, social and behavioral, including handling, holding and puffing

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Figure 4. Participants’ smoking status after 24 weeks of electronic cigarette use. This illustration was developed based on the findings of the study by Polosa et al. [12].



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a cigarette) associated with smoking [36,37]. When the smoker stops smoking, those rituals are no longer there, but the need for the ritual still exists and this is an important cause of relapse. Given that both nicotine- and smoking-related cues appear to control cigarette craving and withdrawal symptoms, electronic cigarettes – by supplying nicotine and by mimicking the rituals associated with cigarette smoking – may be used as an efficient smoking cessation tool [12,27,28]. Also, when we bear in mind that nicotine per se does not cause much risk when separated from inhaling smoke, switching to the electronic cigarette equates to quitting in exposure terms.

Results from recent surveys support the idea that electronic ciga-rettes may be effective in helping smokers quit. In a large internet survey of 3587 electronic cigarette users [10], most respondents (up to 96%) reported that the electronic cigarette helped them quit or reduce their smoking. They also stated that electronic cigarettes were used to avoid relapse. Most ex-smokers in the sample (79%) feared they might relapse to smoking if they stopped using the electronic cigarette. Heavner et al. enrolled 303 users, most of whom lived in the USA (72%) or Europe (21%), via email and links on various blogs and forums [212]. The online survey was conducted by a UK electronic cigarette company and the data was evaluated by independent university researchers. Most (79%) were using electronic cigarettes as a complete replacement for smoking, with another 17% using them as a partial replacement. Health improvements were reported for general health (91%), smoker’s cough (97%) and ability to exercise (84%), and none reported

that these were worse. In the survey of Siegel et al., the prevalence of smoking abstinence among the 222 electronic cigarettes users was of 31% at 6 months [38]. Of those using the elecronic cigarette more than 20-times per day, 70% were nonsmokers at 6 months. Goniewicz et al. surveyed 257 users in Poland to investigate patterns of use [39]. Of the 170 users who completed the sur-vey, 83% were regular smokers when they began using elecronic cigarettes and 66% declared they were not smoking. Almost all (98%) used their electronic cigarettes every day. Nicotine levels used ranged from zero nicotine (3%) to higher than 16 mg per cartridge (25%), with 41% using 8–16 mg per cartridge.

These findings indicate that electronic cigarettes may be an effective aid to smok-ing cessation, and therefore merits further evaluation for this purpose.

Electronic cigarettes: potential for public health benefitsWhen given only the options of smoking or completely giving up nicotine, many smokers will not give it up and will keep on smoking, thus exposing themselves to

increasing health risks. However, if it is considered that nicotine per se does not cause high risk, a third option is also available to smokers; the reduction of smoking-related diseases by taking nicotine in a low-risk form. Tobacco harm reduction (THR), the substitution of low-risk nicotine products for cigarette smoking, is likely to offer huge public health benefits. THR empowers smokers to gain control over the consequences of their nicotine addiction. Harm reduction is particularly compelling for the use of nicotine because so many people have such a strong propen-sity for using it. Harm reduction is arguably the most complex, controversial and divisive issue in tobacco control today [40].

Besides the convincing example of Swedish snus (a type of finely ground moist snuff that delivers significant levels of nicotine) as a successful THR strategy [41–43], electronic cigarettes may prove to be an even more attractive long-term alternative because of their similarities to smoking, including the hand-to-mouth repetitive motion and the visual cue of a smoke-like vapor. Of course, these products may contribute to tobacco addiction, but the dream of a tobacco-free, nicotine-free world is just that – a dream. This is owing to nicotine’s estalished beneficial effects, such as an improved ability to concentrate, pay attention and remember, as well as the capacity for relieving symptoms of mood impairments [21]. Although much more research is required, early results show indications that electronic cigarettes could be effective for helping long-term, inveterate smokers to become abstinent from inhaling smoke. Health improvements enjoyed by switchers do not dif-fer from health improvements enjoyed by nicotine abstainers. In

Table 2. Positive and negative aspects of electronic cigarettes.

Advantages Disadvantages

Not known to cause fires or burns Mislabeling and leakiness of liquid

Beneficial effects on health (improved breathing and less coughing)

Small percentage of the population is sensitive to propylene glycol (dry mouth and throat)

No tobacco smoke odor or bad breath Some flavors have a lingering fragrance

Less toxic than tobacco smoke Trace amounts of TSNAs present in some formulas

Mimics sensation in the throat of inhaling smoke

Throat sensation dependent on hardware used and liquid composition

The gestures or actions are similar to smoking

Equipment is heavier than traditional cigarette and puffing technique requires some training

Facilitates smoking abstinence Some users only manage to reduce the number of cigarettes smoked

Relieves withdrawal symptoms and craving for tobacco

Relief of withdrawal symptoms varies, affected by quality of equipment and nicotine strength of liquid

In theory it can be used everywhere, but adequate regulation for its use in public places is required

Owing to few studies on the potential risk to bystanders, some communities are outlawing indoor use

No ash, dirt or burned clothes Environmental concern about safe disposal of cartridges and batteries

TSNA: Tobacco-specific nitrosamine.



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exposure terms, switching to the electronic cigarette equates to quitting. If sufficient numbers of smokers can transfer their nico-tine dependence to the less-harmful electronic cigarette, millions of lives could be saved.

Several surveys paint a picture of the typical electronic cigarette consumer as a long-term smoker who has tried repeatedly to quit [9,10,38,212]. The median age of respondents ranges from late 30s to mid-40s. The percentage of respondents using the electronic cigarette as a complete replacement for smoking ranges from 31 to over 79%. Most individuals who did not stop smoking completely reduced the number of cigarettes smoked. Over 90% reported that their health had improved. When asked the main reason why they chose to use an electronic cigarette, 64.6% stated “to continue to have a ‘smoking’ experience, but with reduced health risks.” In actual fact, smokers gaining control over the consequences of their nicotine addiction by switching to an electronic cigarette are already putting the basic principles of THR into practice. This strategy is cost effective and accessible today to almost all smokers.

It is of paramount importance that the government and trusted health information sites provide accurate and truthful information about the relative risks of smoking and alternatives to smoking. If the public continues to be convinced that electronic cigarettes are as harmful as (if not even more harmful) than smoking, millions of smokers will be dissuaded from switching to a much less hazardous alternative. In a recent editorial published in the British Medical Journal, Ron Borland commented that by allowing these products to be sold in the UK, the government’s Cabinet Office seems to be taking the approach with the greatest potential for public health benefits [44]. The Royal College of Physicians has stated: “It is possible that alternative nicotine products could provide a safer long-term substitute for cigarette smoking. If so, this could benefit individual and public health” [212]. The electronic cigarette may provide a safer long-term substitute for cigarette smoking.

Electronic cigarettes: regulatory issuesObviously, these products need to be adequately regulated. Internet marketing of the electronic cigarette and the inadequacy and misapplication of import product codes, however, impede systematic regulation. Thus far, there have been heterogeneous regulatory responses ranging from no regulation to complete bans. In Italy, Categoria electronic cigarettes (including those with nico-tine) are the only ones approved by the Italian Institute of Health. The WHO’s Study Group on Tobacco Product Regulation advised a precautionary approach to electronic cigarettes [1] and, with few exceptions, most national regulatory agencies have also adopted a similar stance. The basis for these regulatory decisions is uncertain, and more research on electronic cigarettes must be conducted in order to ensure that the decisions of regulators, healthcare providers and consumers are based on science.

However, whether this should occur before allowing the prod-ucts on to the market or accepting that they might continue to be allowed is debated. According to those who argue that research data should be available before allowing the electronic cigarette on to the market, the first priority is to characterize the safety profile of these products, including in long-term users [45]. Nevertheless,

it is not in the best interests of public health to halt the marketing of electronic cigarettes until these long-term studies are com-pleted. All research to date shows much higher rates of smok-ing abstinence among users when compared with other meth-ods. Furthermore, the complete absence of any serious adverse events reported during the 7 years the products have been in use worldwide should be compared with the severe health hazards of continued smoking.

In the absence of specific recommendations for regulation, it is important that electronic cigarette manufacturers and distribu-tors must comply with the best possible quality standards. For example, future regulations should ensure that the liquid in the electronic cigarette is manufactured under sanitary conditions and uses pharmaceutical-grade or US Pharmacopoeia-grade ingredients, and that a listing of all ingredients, additives, any potentially harmful constituents and information on the percent-age of nicotine present, if any, should be explicitly stated. Also, labels should not be required to display misleading messages such as, ‘this product is not a safe alternative to cigarettes’. A more accurate message would be, ‘this product may be less hazardous than cigarette smoking.’ In the authors’ opinion, the electronic cigarette industry should welcome regulation as a way to legiti-mize their business, and recognize that regulation may ultimately help to prove the electronic cigarettes to be a safer alternative to traditional tobacco products.

ConclusionTobacco smoking is a global pandemic, affecting an estimated 1.2 billion people, which poses substantial health burden and costs. With nearly 6 million tobacco-related deaths annually, smoking is the single most important cause of avoidable prema-ture mortality in the world [46]. Death is mainly caused by lung cancer, coronary heart disease, chronic obstructive pulmonary disease and stroke [47,48]. According to the WHO Framework Convention on Tobacco Control, a significant reduction in the health burden of tobacco in the medium term may be obtained by encouraging cessation among smokers [49].

However, in reality, the efficacy of current smoking-cessation interventions is modest and far too many smokers are unwilling or unable to quit. Thus, a broader range of interventions are needed in order to bring more smokers into treatment and increase the num-bers who are motivated to make attempts to quit. Alternatively, tobacco smoking could be replaced by ‘vaping’. Given that neither tobacco nor combustion are necessary for its operation, it is likely that electronic cigarettes could be used as a lower risk substitute for tobacco cigarettes. Electronic cigarettes may prove to be the most promising solution for the reduction in the use of traditional cigarettes and their associated risk, with the positive features of these products clearly outweighing the negative features (Table 2). Clearly, other valid options for tackling nicotine dependence in smokers exist, but it is still a personal choice of how to introduce nicotine into his/her body. Each individual smoker should find the best way to reduce or eliminate his or her own smoking. In theory, at least for Westernized cultures, ‘vaping’ is a far better option than smoking, and it could save millions of lives.



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Expert commentaryFor many years, several experts in tobacco control have been hoping to witness an efficient method to deliver nicotine. The electronic cigarette has the potential of being such a method, because it can provide smokers with what they want thanks to the combined effect of hand-to-mouth motion and nicotine. It is also much safer than a lit cigarette. In the author’s opinion, smokers who are unable or unwilling to quit represent a formidable target for health interven-tion. To this end, the electronic cigarette is an opportunity not to be missed. The urge to better understand the potential of their role in the smoker’s life prompted us to set up several trials to investi-gate the electronic cigarette and from this ongoing experience we have learned several things. First, smokers appear to be buying them to reduce cigarette consumption and, most importantly, to continue having a ‘smoking’ experience, but with reduced health risks. Second, the results from the clinical trials are promising and agree with what seems to be occurring in the real world, that almost all ‘vapers’ are former smokers and many report not actively trying to quit until they tried electronic cigarette. Third, these products appear to be much safer than tobacco cigarettes and comparable in toxicity to conventional nicotine-replacement products. Fourth, not all electronic cigarettes are the same; earlier models are ham-pered by inadequate manufacturing standards, but much improved models are in progress to foster their wider adoption and a steeper reduction in smoking prevalence. Finally, providing truthful infor-mation about this product may convince smokers that ‘vaping’ is one of the most harmless method of obtaining nicotine.

Five-year viewElectronic cigarettes can substantially decrease cigarette con-sumption without causing significant side effects, but large and carefully conducted controlled trials will be required before a definite answer about the efficacy and safety of these devices can be formulated. Some of these trials are now in progress in Italy [209,210] and New Zealand [211] and we anticipate that many more will follow in the coming years. This new research will also have to address long-term safety (including in patients with chronic respiratory diseases), role of nicotine dose titration and flavors/additives in guarding against relapse, reduction in the prevalence of tobacco-related diseases and efficacy in challeng-ing subgroups of smokers (e.g., psychiatric patients and young adults). Moreover, research in the area of passive ‘vaping’ would be important for legislators. Hopefully, this research will form the basis for firm regulatory decisions. Moreover, in the future, liquid in these products shall be manufactured under sanitary conditions, using pharmaceutical grade nicotine.

Financial & competing interests disclosureR Polosa has received lecture fees from Pfizer and he has served as a consul-tant for Arbi Group Srl (Milano, Italy), the distributor of the Categoria™ e-Cigarette. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Although a significant reduction in the health burden of tobacco may be obtained by encouraging cessation among smokers, far too many smokers are unwilling or unable to quit. Smoking is a very difficult addiction to break.

• Currently available smoking-cessation medications are only modestly effective. Thus, a broader range of interventions are needed in order to bring more smokers into treatment and to increase the numbers who are motivated to make attempts to quit.

• Alternatively, tobacco smoking could be replaced by using lower-risk substitutes for tobacco cigarettes. Given that neither tobacco nor combustion are necessary for its operation, it is likely that electronic cigarettes could be used as a lower-risk substitute for tobacco cigarettes.

• Besides delivering nicotine, electronic cigarettes may also provide a coping mechanism for conditioned smoking cues by replacing some of the rituals associated with smoking gestures (e.g., the hand-to-mouth action of smoking).

• Electronic cigarettes may prove to be the most promising solution for the reduction in the use of traditional cigarettes and their associated risk. Around the world many people report buying electronic cigarettes to help them quit smoking, in order to reduce cigarette consumption and to relieve tobacco withdrawal symptoms due to workplace smoking restrictions.

• Recent research shows that electronic cigarettes can substantially decrease cigarette consumption without causing significant side effects.

• Large and carefully conducted randomized controlled trials will be required before a definite answer about the efficacy and safety of these devices can be formulated.

• Electronic cigarettes need to be adequately regulated and more research on these products must be conducted in order to ensure that the decisions of regulators, healthcare providers and consumers are based on science.

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The emerging phenomenon of electronic cigarettes

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