Pros and Cons of Long-Term Use of Nicotine Replacement Therapies: A Qualitative Study
Smoking has long been known to be the single most important preventable cause of premature death in developed countries [1,2]. To combat mortality rates caused by smoking, several activities and campaigns have been launched in the western world, and as a result, the prevalence of smoking has decreased drastically since the 1960s. However, the decrease has become stagnant in recent years . An action to counter this stagnation has been the introduction of the concept of harm reduction in the UK, targeting smokers unable or unwilling to quit all nicotine products, e.g., the possibility of substituting tobacco with long-term nicotine replacement therapy products (NRTs) . A gradual expansion of the marketing licenses of NRTs has occurred since the early 1980s when nicotine gum was first marketed and sold by prescription only. Nicotine was thought to be, if not the sole cause, at least the primary cause of addiction to smoking. Concerns, therefore, included NRTs posing an addiction liability and the risk that prolonged use might cause adverse health effects [4,5].
However, with no serious adverse effects of NRTs yet proven [6,7], the shift from smoking cessation as the ultimate and only goal to a compromise of harm reduction seemed possible [4,8- 12]. To increase the effectiveness of NRTs, the products needed to be as easy to access as cigarettes, resulting in a switch first from prescription-only drugs to over-the-counter availability and then to a variety of NRTs made available for retail sake . Likewise, the indication for use of NRTs has expanded from an initial treatment course entailing three months use upon smoking cessation to now including use to achieve smoking reduction and long-term use if the alternative is relapsing to smoking.
The prevalence of long-term use of NRTs following smoking cessation attempts has been estimated to be approximately 1% in the USA . In Denmark, the results from a national survey in 2012 on the smoking habits of the Danish population showed that 1.3% of the adult Danish population had used NRTs for more than 12 months .
Early research regarding the long-term use of NRTs primarily focused on prevalence, safety and the characteristics of long-term users, estimating that heavy smokers were more liable to become long-term users of NRTs [6,15-17]. Research also showed that long-term use was positively related to the speed of nicotine delivery from faster-acing NRTs . With the absence of proof regarding serious adverse effects of NRTs, more recent research has focused on harm reduction in terms of smokers’ willingness to substitute smoking with NRTs or smokeless tobacco and the effect of dual use of cigarettes and NRTs on smoking cessation [18-22]. Perceived benefits of smoking cessation include improved health, well-being, self-esteem, finances, physical appeal and social approval, whereas perceived risks are weight gain, negative affect, decreased concentration, social ostracism, loss of enjoyment and craving [23-25].
Quitting the use of NRTs may entail a risk of relapsing to smoking. Etter  found that of 302 ex-smokers using nicotine gum for more than 3 months, 42% feared to relapse to smoking if they quit using the gum, whereas 82.8% reported feeling addicted to nicotine gum . In addition, a study by Borup et al.  found that among 92 ex-smokers who used NRTs for more than 12 months, 88% wished to quit using NRTs because of product costs, addiction and concerns regarding adverse health effects ; hence, the use of NTRs does not appear to be entirely unproblematic.
With tobacco addiction being recognized as a relapsing chronic illness , the idea of achieving harm reduction with NRTs as substitutes for cigarettes seems appropriate if long-term use prevents relapse . However, with previous research showing that the use of NRTs is not solely motivated by the prevention of relapse to smoking and that a vast majority of individuals would like to quit using NRTs, the aim of this study was to investigate the experiences of long-term NRTs users in regards to the pros and cons of NRTs use, the risk of relapse to smoking and the motivation to quit NRTs. To the best of our knowledge, these questions have not previously been investigated qualitatively.
The design of the study consisted of semi-structured interviews to explore in depth perspectives on individual NRTs use yet also allow for comparability across the interviews [30,31]. Both former smokers now using NTRs and current smokers also using NTRs (dual users) were eligible for the study in order to capture experiences and difficulties with using NRTs, to highlight the obstacles of quitting smoking for dual users despite the use of NRTs, and to explore the reasons for relapsing in order to gain insight into experiences not mentioned or considered by the ex-smokers.
The first author (GB) conducted the interviews, either in the participants’ homes or workplace or at the university campus, based on the participant’s preference. The interview guide consisted of four themes: 1) the timeline from when the participants had begun using NRTs, 2) how the smoking cessation process had been experienced, 3) how they experienced using NRTs at the current time, and 4) what they expected the future to hold concerning their NRTs use. Similarly, the dual users were asked to recount their decision to begin using NRTs, their current use and their prospects for the future concerning smoking and NRTs.
The construction of the interview guide was based on the guidelines given in Smith, Flowers and Larkin (2009), recommending open and expansive questions that allow participants to talk freely, providing in-depth knowledge of thoughts and experiences. Probing was applied to elaborate on experiences that seemed especially important to the individual participant .
Furthermore, fixed questions were applied in each interview regarding the age of the participants, the amount of NRTs used per day, and former smoking history.
The initial recruitment was based on the participant list from a former survey study of long-term users of NRTs in Denmark, where participants willing to participate in further investigations were requested to state their contact information . Participants where purposefully selected  based on the criteria that 1) they were former smokers, 2) they were at least 18 years of age, and 3) they had used NRTs for more than 12 months on a daily basis to ensure that they had adequate experience. From the survey, 18 participants who met the inclusion criteria were contacted, and nine participants agreed to participate in the study. Three dual users were included in the study. An additional round of recruitment was conducted to obtain enough participants to ensure saturation of results . Additional recruitment techniques included snowballing, i.e., recruitment from other interviewees, friends, and colleagues who knew long-term users of NRTs (9 participants) and recruitment from pharmacies (1 participant) [33,35].
Ethical approval was not required in the Danish setting, as the primary purpose of this investigation did not entail questions on sensitive topics. The study followed guidelines of the National Committee of Health Research Ethics Guidelines, which complies with international standards. All participants were informed of the purpose of the study either verbally or in writing, and all of them gave their oral consent to participate.
The interviews were recorded and transcribed verbatim. The analysis of the transcription from the initial nine interviews was hereafter based on the guide given by Smith, Flowers, and Larkin, following an iterative and inductive cycle [32,36]. Tables for primary analysis for each participant were produced, containing initial notes, and emergent themes. These emergent themes were subsequently assembled to superordinate themes for each participant. When the individual analyses for the first nine participants were concluded, a master table of themes was drawn, highlighting similarities between the themes. The remaining ten interviews were then analyzed deductively, supplementing existing superordinate themes aiming at saturation while maintaining an openness to new themes . The two co-authors read interview transcripts and commented on the conducted analysis to reach consensus.
The study comprised 16 ex-smokers and 3 dual users of tobacco and NRTs. The interviews lasted from 40 to 75 minutes. An overview of the interviewees is provided in table 1. The ex-smokers consisted of eight men and eight women with an average age of 54,2 years (range: 37-68). The ex-smokers were primarily former heavy smokers with an average smoking history of 19.6 cigarettes per day (range 6.5-30, N=15); one was a former pipe and cigar smoker. The NRTs used were primarily 2 mg nicotine gum (N=14), with one person using 2 mg sublingual tablets and one using a nicotine inhaler. The mean use of NRTs per day was 13.2 (range 6-22,5), and the mean number of years of NRTs use was 8.5 (range: 2-15). None of the ex-smokers feared to relapse to smoking. The dual users consisted of one man and two women who were all 40-49 years of age. Their current average use of NRTs was 6 NRTs per day (range 3.5-10), and their current smoking habit included 7.8 cigarettes per day (range 3.5-10). All dual users used 2 mg nicotine gum. Interviewees were predominantly middle-class citizens.
Non-nicotinic factors and the importance of taste, texture and the process of chewing
Some interviewees used NRTs for several years before quitting smoking entirely. The use of NRTs was often described as a necessity to be able to endure a day’s work without becoming unfocused, and where smoking was experienced and remembered as enjoyable, the use of NRTs was described in terms of need. The substitution had demanded extreme willpower for some, with NRTs failing to stimulate all the senses that smoking did and lacking the social element.
INT13: Two very different things. Is it out of need right? The other (smoking red.) was out of desire. This is not desire; it’s need because I have decided that I don’t want that smoke in my lungs. However, there are many… There is a lot of delight in smoking a cigarette and having a cup of coffee… And sitting with some nice people and smoking a cigarette, one thought, then… (…) Eh, and that’s not at all the same… not… you can’t even compare the two things (p. 16)
For some of the interviewees, the transition had, however, been experienced as quite easy, describing how the final decision to quit smoking had left no room for relapse, and they, therefore, managed to quit overnight.
Taste, texture, the presence of gum in the mouth, the ‘process of chewing’ and the ‘strong sensation’ of nicotine were important aspects of using NRTs. The majority of the interviewees used only their favorite taste and product, which made it quite clear that the process of using nicotine gum entailed elements other than extracting the nicotine from the gum alone. Some participants described having a clear need for the stimulant effect, whereas others speculated that it was less about the need for nicotine than about the ‘taste’. However, substituting the nicotine gum with regular gum was not straight forward, as nicotine gum was experienced as maintaining flavor significantly longer, and regular gum lacked the right texture and the ‘strong sensation’ caused by the nicotine. The chewing had also become constant for some, who did not allow the gum to rest on the cheek as it is intended to, and with one piece of gum replacing the other in an automated fashion.
*Not motivated/no intention of quitting NRTs
#Does not think relapse to smoking is possible
Tabel 1. Overview and description of interviewees.
INT9: It’s a habit to chew. That’s also a habit that I have developed. I have to chew. I need to chew.
The worst case scenario was described by one interviewee, whose favorite gum had been taken off the market for a while, resulting in a relapse to smoking because the interviewee disliked the other tastes available. Interestingly, one of the dual users, INT18, had developed a co-dependency on cigarettes and NRTs using nicotine gum immediately after smoking, not so much for the extra nicotine but, again, because of a preference for the taste and texture. When asked what would happen if INT18 depleted the supply of NRTs, the answer was that she would smoke fewer cigarettes because of a dislike of the aftertaste.
Health risks associated with smoking vs. NRTs
Some of the interviewees had developed deterioration of their lung capacity, suffering from repeated pneumonia and bronchitis while still smoking, and these problems were alleviated when they substituted NRTs. Others expressed being able to breathe more easily and an alleviation of their ‘smokers cough’. The experience of improved health therefore not only increased the satisfaction of having achieved smoking cessation but also diminished the belief in NRTs being hazardous.
INT14: Yes definitely. Huge. A huge difference. You know, I can feel that NRTs don’t tire out my body. I feel that I don’t, eh, hurt my lung capacity, so I don’t ruin my physique by using NRTs. While it only took about 6-8 cigarettes, it literally ruined my shape. (…) Where nicotine gum didn’t… I haven’t noticed thatit affects my immune system in any way. Eh, so that was a huge – and that is probably also why, in reality, the ‘yes-ish’ feeling that you don’t smoke. And perhaps even a ‘thank you, nicotine gum’ sense of ‘I don’t have to quit using you’ or something like that.
Most interviewees had not discussed their use of NRTs with any healthcare professionals, and the overall impression wasthat physicians did not care much about the use of NRTs as long as the interviewees had quit smoking.
Information on adverse effects was primarily obtained from the package leaflet or the Internet. A couple of the interviewees who had spoken to their physicians had received conflicting messages. INT1 had suffered a stroke a couple of years earlier, and the physician responsible for follow-up treatment had reassured her that the use of NRTs would not impact her health negatively and that NRTs had not contributed to the stroke. Contrarily, INT9 was told from her primary physician that the prolonged use of NRTs was bad for her heart.
This information caused INT9 to halve her consumption of NRTs but did not make her quit using the products, as another physician had previously told her that NRTs were not harmful. Short-term use of NRTs was regarded as safe by all, but the long-term use of nicotine was suspected to be potentially harmful.
INT10: Because basically I have an assumption that it’s not the nicotine that’s the dangerous part of smoking, and it’s the tar and all the other additives, eh, but I am aware that it may not be healthy to use for the next 10-15 years, and you know (…) I at least don’t have enough knowledge concerning whether its harmful or not. And that is what makes we wish that I wouldn’t. (p. 5)
Several interviewees agreed that the underlying fear of NRTs causing harm was the fact that nicotine is derived from tobacco. These uncertainties also led to some of the interviewees interpreting bodily symptoms as being caused by NRTs. The symptoms described were nausea, heart palpitations and a tightening sensation in the chest. The interviewees’ reaction to the symptoms was to reduce NRTs for a short period and wait for the symptoms to cease and then return to a normal level of NRTs use. However, the interviewees exhibited a pragmatic approach to the valuation of the potential harm of NRTs, considering NRTs to be not much worse than other stimulants, such as sugar, caffeine, and alcohol, or not more carcinogenic than breathing in pollution while living in a big city. All the ex-smokers agreed that proof of serious adverse effects of NRTs would be needed to motivate them to quit.
The interviewees’ thoughts on addiction deduced from their use of NRTs and prior smoking gave rise to many contradictingstatements where addiction in itself largely was considered a highly negative thing that all interviewees would like toeliminate. A majority of the interviewees had a presumption of being prone to addiction. A few mentioned their belief thatthey were genetically predisposed, whereas others seemed to think of it more in terms of a personality trait. In practice, this predisposition for addiction meant that quitting NRTs would include transferring the addiction to something else.
INT8: I can’t picture myself as an alcoholic, right? And I can’t picture myself as a smoker either right? But, then, what is it? I still take something that I am addicted to. So I have that concern… if you have to be addicted to something. I also know that it isn’t just… I, of course, meet those once in a while – people other than myself, that I can see – why is it that they don’t just quit this (smoking red.), right? I think that is strange. They are… many of them are of course essentially reasonably sensible people in all other respects. And can use their heads in all sorts of other stuff, but then why do they become addicted to something? It can be a very strange thing to understand, and I don’t understand it myself. And I can’t see how I am supposed to solve it really. And then I’m thinking that I found a very good path really if that’s the way it is. (p.10)
The overall argument was therefore that if the sum of all voices is constant and if one had to substitute smoking with something else, then the use of NRTs was acceptable, a lesser evil.
Furthermore, NRTs had assisted the interviewees in quitting smoking, and it now helped them to avoid being tempted tosmoke at social gatherings, helped them concentrate and control negative affect, and prevented some of the intervieweesfrom eating excessively or acted as a substitute for sweets. Use of NRTs was described as convenient and discrete, as NRTscould be used everywhere, making it unnecessary to go outside to smoke or to wait for a break during a long meeting. Several of the interviewees also described the need for NTRs to be less urgent than the need for smoking had been. This reduced urgency also increased the experience of control, as many of the interviewees described being able to go without NRTs for longer periods of time than they could endure when still smoking.
INT2: When you smoke 25 cigs, and that’s a lot to smoke. It’s the first thing you do when you get up, and it’s the last thing you do before you go to bed. And, all the time, ‘oh those bloody meetings’, ‘can’t we take a break’ and all that.
The use of NRTs was also described as something private and as an expression of personal freedom and choice. The cons of using NRTs included depleting the supply of NRTs, which still triggers feelings of anxiety, similar to that experienced whilestill smoking, thus underscoring the prevalence of addiction.
Social environment of smoking vs. NRTs
All the ex-smokers were convinced that they would not relapse to smoking even if they quit using NRTs. In addition to the major health risks associated with smoking, statements regarding physical aversion to the taste and smell of smoke were given, and the participants did not want to be the object of the social stigma associated with smoking were mentioned.
INT11: No. I probably did the first 5 years (felt tempted to smoke red.). But now, it has also become associated with being a loser. Well, it’s also really inconvenient and associated with losers and… Well. No. I really can’t see it.
For all of them, an unsuccessful quit attempt would most likely result in a relapse to NRTs rather than smoking. Althoughmost of the interviewees described not being ashamed of using NRTs, several described the discomfort of drawing attentionto themselves and their NRTs use. Some discussed their dependence on NRTs as something they would not want to signal a lack of control in front of colleagues who did not share the same dependence.
INT 14: It has something to do with wanting to present an image of being in control. Eh, and sitting there chewing gum, it – that is, nicotine gum – well, that’s an addiction. Well, eh, and that you don’t want to signal… that I am dependent on something (…) You know, if you take the gum in a situation related to work, for example. Then, its… well, I think I take the gum because I feel some kind of unease. That, of course, is not something you want to display in a working situation, that you have some kind of unease in your body. So, for me, it’s like… well, I would say that I actually hide mine (…) that it, eh, that, of course, one wants to be perfect. Eh, or completely in control. And, eh, I think that I’m lacking in that bit.
As a solution, some of the interviewees re-packaged their gum in small boxes to give the impression of containing regulargum, circumventing the noise of the blister packs. Some interviewees had experienced being confronted by others abouttheir use of NRTs and being labeled as ‘still addicted’. Others felt they were met with praise for having succeeded in quittingsmoking, and no negative value was given to their continued use of NRTs.
Although all interviewees agreed that the use of NRTs entailed a cost, some estimated that they spent less money on NRTsthan on smoking and, in that sense, saved money compared to their earlier experience; by contrast, others viewed NRTs asa very expensive vice. Those contemplating substituting NRTs with regular gum argued that this was almost as expensive as NRTs. Therefore, the cost of NRTs motivated only one of the interviewees to quit.
The dual users
All three dual users had succeeded in quitting smoking previously, also by using NRTs. Common for all three users was that they had relapsed to smoking during periods of their lives that entailed major emotional stress, including the death of aparent, divorce and work-related stress, and NRTs had been experienced as insufficient. INT17, who had quit smoking for 5 years before relapsing, felt that the sustained use of NRTs had eased the relapse to smoking, as the addiction to nicotinewas still present. Hence, the gap had not been as wide as it would have been if INT17 had quit all nicotine products. Twointerviewees described the difficulty in reaching a level of motivation to quit again that was the same as the level initiallyleading them to quit in their previous attempt, whereas the third interviewee felt confident that success was possible in the near future.
This study aimed at investigating the perceived pros and cons of long-term NRTs use, the risk of relapse to smoking and the motivation to quit NRTs. The non-nicotinic factors of using NRTs were found to play a significant role in the continued use of NRTs. Despite the conviction that NRTs were less harmful than smoking, participants still had uncertainty regarding the safety of NRTs. Additionally, the convenience of using NRTs and the view of NRTs as a ‘lesser evil’ permitted their continued use. The primary drawback was the experience of addiction, and the cost of NRTs was a minor drawback. None of the ex-smokers feared to relapse to smoking.
Non-nicotinic factors have been described as being important obstacles to quitting smoking [37,38]. An important findingof this study was, therefore, the detailed description of the non-nicotinic factors associated with feeling addicted to nicotinegum. These factors, including favourite taste, texture, the presence of the gum in the mouth and the ‘strong’ sensationcaused by nicotine, contributed not only to sustained use of NRTs but also to increased use or, in the worst case, to a relapse to smoking if a participant’s favourite taste were withdrawn from the market. It is possible to obtain free sampleswithout nicotine at pharmacies, but they cannot be purchased in retail stores. Better access to nicotine-free gums would bean appropriate option for users wanting to reduce their nicotine intake. The importance of these non-nicotinic factors, in
association with the use of NRTs, has yet to be investigated further. Contrary to the new dependencies on non-nicotinic factors via the gum, an aversion to the taste and smell of tobacco smoke had developed in these users and was used, in addition to the health risk of smoking, as an argument to not relapse to smoking.
Benefits and drawbacks of using NRTs
The benefits of using NRTs were enjoyment, convenience, improved health, increased concentration, prevention of weightgain and social acceptance. The drawbacks were primary concerns regarding long-term health risks and the sustained addiction and, to a lesser extent, the financial cost. Research on smokers’ expectancies for abstinence has identified perceived benefits as improvements in long-term health, well-being, self-esteem, finances and social approval. Identified perceived drawbacks include weight gain, negative affect, difficulty concentrating, loss of enjoyment, craving and increased use of other stimulants [23-25]. It, therefore, seems that the long-term use of NRTs yields the expected benefits of quitting smoking to some extent while still avoiding some of the expected drawbacks. However, health and social acceptance are ambiguous, perceived as both benefits and drawbacks.
Several studies have found that smokers believe NRTs to be harmful to health and cause addiction. These beliefs, however,decrease with increasing socioeconomic levels, number of cessation attempts and former experience with using NRTs [39-41]. Our study, therefore, shows that residual worry remains in long-term users. However, the possible harm is not interpreted as worse than many other risks we encounter in everyday life, and in the absence of solid proof of NRTs being harmful, this fear has not motivated cessation. However, the interpretation of bodily symptoms being caused by NRTs may in worst-case scenarios mask serious illness and cause delays in seeking medical attention. More clear communication from a credible source on the benefits of using NRTs and encouragement to seek medical advice should be provided.
The continuance of addiction
Three negative aspects regarding the continued addiction were described. One was the predisposition to addiction, thesecond was the appearance of lacking control, and the third was the social reaction and the label of an addict. In Stuber etal. , stigmatisation in regards to genetic predisposition to a negatively valued quality, such as addiction, is explained interms of the perception of the individual being fundamentally different from others and the idea that the problem is seriousand persistent . This may explain the self-reproach and the dislike of drawing attention to the use of NRTs, as somestigma is adherent to ‘addiction’ and not only to smoking, even though the experienced stigma was less than that associated with smoking. However, Keane  argues that the liberalisation of NRTs and the conversion of medical control to consumer products may lead to a normalised version of addiction, and a transformation of NRTs users as rational consumers who are responsible and prudent enough to choose the ‘safe’ product to remedy their condition . Based on this study, however, this level of acceptance has not yet been reached. However, individuals continued their addiction rather than being motivated to quit, given the discreteness of NRTs and the lesser stigma associated with NRTs.
Strengths and limitations
Although the participants were selected to compose a homogenous group, this approach did not intentionally require mostof the participants to be over the age of 40. This similarity in age may, therefore, limit the transferability of the study to other age groups . However, from former studies involving long-term users of NRTs, it seems that long-term NRTs users are primarily middle-aged users; hence, the participants in the present study may very likely represent the bulk of longterm NRTs users [21,26,27]. Hence, transferability to other age groups may not be that important at this point. The strengths of the study were the quality of the empirical data, as the interviewees were open to telling their stories in an honest and reflective manner, and the attention that was given to the analysis of each interview before focussing on similarities across the interviews . The inclusion of dual users contributed additional understanding of the experience of long-term use and the risk of relapse, but the focus of the dual users was primarily on how to regain motivation to quit smoking and less on the use of NRTs. A study on relapsed dual users alone may, therefore, provide a better understanding of this experience.
None of the ex-smokers feared to relapse to smoking. Non-nicotinic factors were found to play an important part in developing an addiction to NRTs. The use of NRTs yields some of the expected benefits and helps avoid some of the expected drawbacks of smoking cessation in terms of contributing enjoyment, convenience, improvements in health, better concentration, and avoidance of weight gain. However, the drawbacks of using NRTs were still a concern in terms of long-term health effects and continued addiction.
- McBride D, Barrett SP, Kelly JT, Aw A, Dagher A et al. Effects of expectancy and abstinence on the neural response to smoking cues in cigarette smokers: an fMRI study. Neuropsychopharmacology. 2006, 31(12): 2728-2738.
- Wilson SJ, MA Sayette, JA Fiez. Prefrontal responses to drug cues: a neurocognitive analysis. Nat Neurosci. 2004,7(3): 211-214.
- Tapert SF, Cheung EH, Brown GG, Frank LR, Paulus MP et al. Neural response to alcohol stimuli in adolescents with alcohol use Archives of General Psychiatry. 2003,60(7): 727-735.
- Sell LA, Morris JS, Bearn J, Frackowiak RS, Friston KJ et al. Neural responses associated with cue evoked emotional states and heroin in opiate addicts. Drug and Alcohol Dependence. 2000,60(2): 207-216.
- Grant S, London ED, Newlin DB, Villemagne VL, Liu X, Contoreggi C et al. Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci USA. 1996, 93(21): 12040-12045.
- Garavan H, Pankiewicz J, Bloom A, Cho JK, Sperry L et al. Cue-induced cocaine craving: Neuroanatomical specificity for drug users and drug stimuli. American Journal of Psychiatry. 2000,157(11): 1789-1798.
- Hyman SE, RC Malenka, EJ Nestler. Neural mechanisms of addiction: The role of reward-related learning and memory. Annual Review of Neuroscience. 2006, 29: 565-598.
- Fuster JM. Executive frontal functions. Experimental Brain Research. 2000. 133(1): 66-70.
- Desposito M, Detre JA, Alsop DC, Shin RK, Atlas S et al. The Neural Basis of the Central Executive System of Working-Memory. Nature. 1995,378(6554): 279-281.
- Goldstein RZ, ND Volkow. Oral methylphenidate normalizes cingulate activity and decreases impulsivity in cocaine addiction during an emotionally salient cognitive task. Neuropsychopharmacology. 2011, 36(1): 366-367.
- Goldstein RZ, ND Volkow. Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci. 2011,12(11): 652-669.
- Shalev U, JW Grimm, Y Shaham. Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev. 2002,54(1): 1-42.
- Feltenstein MW, RE See. The neurocircuitry of addiction: an overview. Br J Pharmacol. 2008, 154(2): 261-274.
- Belin D, Jonkman S, Dickinson A, Robbins TW, Everitt BJ. Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction. Behav Brain Res. 2009,199(1): 89-102.
- Pierce, R.C. and V. Kumaresan. The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev. 2006, 30(2): 215-238.
- Wise, R.A., Roles for nigrostriatal-not just mesocorticolimbic-dopamine in reward and addiction. Trends Neurosci. 2009,32(10): 517-524.
- Volkow N.D, Fowler JS, Wang GJ, Swanson JM, Telang F. Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol Psychiatry. 2004,9(6): 557-569.
- Daglish MR, DJ Nutt. Brain imaging studies in human addicts. Eur Neuropsychopharmacol. 2003, 13(6): 453-458.
- Volkow ND, Wang GJ, Fowler JS, Hitzemann R, Angrist B et al. Association of methylphenidate-induced craving with changes in right striato-orbitofrontal metabolism in cocaine abusers: implications in addiction. Am J Psychiatry. 1999, 156(1): 19-26.
- Sell LA, et al. Neural responses associated with cue evoked emotional states and heroin in opiate addicts. Drug Alcohol Depend. 2000,60(2): 207-216.
- Tapert SF, Cheung EH, Brown GG, Frank LR, Paulus MP et al. Neural response to alcohol stimuli in adolescents with alcohol use Arch Gen Psychiatry. 2003,60(7): 727-735.
- Volkow ND, Fowler JS, Wang GJ, Goldstein RZ. Role of dopamine, the frontal cortex and memory circuits in drug addiction: insight from imaging studies. Neurobiol Learn Mem. 2002,78(3): 610-624.
- Nitsche MA, et al. Transcranial direct current stimulation: State of the art 2008. Brain Stimul. 2008, 1(3): 206-223.
- Nitsche MA, Fricke K, Henschke U, Schlitterlau A, Liebetanz D et al. Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans. J Physiol. 2003,553(Pt1): 293-301.
- Nitsche MA, Paulus W. Modulation of cortical excitability by weak direct current stimulation-‐-‐technical, safety and functional aspects. Suppl Clin Neurophysiol. 2003, 56: 255-276.
- Nitsche MA, W Paulus. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J Physiol. 2000,527(Pt 3): 633-639.
- Nitsche MA, W Paulus. Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology. 2001,57(10): 1899-1901.
- Nitsche MA, Liebetanz D, Tergau F, Paulus W. Modulation of cortical excitability by transcranial direct current Nervenarzt. 2002,73(4): 332-335.
- Wassermann EM, J Grafman. Recharging cognition with DC brain polarization. Trends Cogn Sci. 2005, 9(11): 503-505.
- Nitsche MA, Loo C. Transcranial direct current stimulation: a new treatment for depression? Bipolar Disord. 2002,4(Suppl 1): 98-99.
- Fregni F, Boggio PS, Nitsche MA, Marcolin MA, Rigonatti SP et al. Treatment of major depression with transcranial direct current Bipolar Disord. 2006,8(2): 203-204.
- Fregni F, Paulo S. Boggio, Michael A. Nitsche, Sergio P Rigonatti, Alvaro Pascual-Leone. Cognitive effects of repeated sessions of transcranial direct current stimulation in patients with depression. Depress Anxiety, 2006.23(8): 482-484.
- Boggio PS, Rigonatti SP, Ribeiro RB, Myczkowski ML, Nitsche MA et al. A randomized, double-blind clinical trial on the efficacy of cortical direct current stimulation for the treatment of major depression. Int JNeuropsychopharmacol. 2008, 11(2): 249-254.
- Bikson M, Bulow P, Stiller JW, Datta A, Battaglia F et al. Transcranial direct current stimulation for major depression: a general system for quantifying transcranial electrotherapy dosage. Curr TreatOptions Neurol. 2008. 10(5): 377-385.
- Boggio PS, Sultani N, Fecteau S, Merabet L, Mecca T et al. Prefrontal cortex modulation using transcranial DC stimulation reduces alcohol craving: A double-blind, sham-controlled study. Drug and AlcoholDependence. 2008, 92(1-3): 55-60.
- Nakamura-Palacios EM, de Almeida Benevides MC, da Penha Zago-Gomes M, de Oliveira RW, de Vasconcellos VF et al. Auditory event-related potentials (P3) and cognitive changes induced by frontal direct current stimulation in alcoholics according to Lesch alcoholism typology. Int J Neuropsychopharmacol. 2012,15(5): 601-616.
- Fregni F, Liguori P, Fecteau S, Nitsche MA, Pascual-Leone A et al. Cortical stimulation of the prefrontal cortex with transcranial direct current stimulation reduces cue-‐provoked smoking craving: A randomized, sham-‐ controlled study. Journal of Clinical Psychiatry. 2008,69(1): 32-40.
- Boggio PS, Zaghi S, Villani AB, Fecteau S, Pascual-Leone A et al. Modulation of risk-taking in marijuana users by transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC). DrugAlcohol Depend. 2010, 112(3): 220-225.
- Fregni F, Orsati F, Pedrosa W, Fecteau S, Tome FA et al. Transcranial direct current stimulation of the prefrontal cortex modulates the desire for specific foods. Appetite. 2008,51(1): 34-41.
- Kuo MF, Nitsche MA. Effects of transcranial electrical stimulation on Clin EEG Neurosci. 2012,43(3): 192-199.
- Jeon SY, Han SJ. Improvement of the working memory and naming by transcranial direct current stimulation. Ann Rehabil Med. 2012,36(5): 585-595.
- Fertonani A, Rosini S, Cotelli M, Rossini PM, Miniussi C et al. Naming facilitation induced by transcranial direct current Behavioural Brain Research. 2010,208(2): 311-318.
- Fiori V, Hueckel-Weng R, Birbaumer N, Plewnia C et al. Transcranial Direct Current Stimulation Improves Word Retrieval in Healthy and Nonfluent Aphasic Subjects. Journal of Cognitive Neuroscience. 2011,23(9): 2309-2323.
- Dockery CA, Hueckel-Weng R, Birbaumer N, Plewnia C et al. Enhancement of Planning Ability by Transcranial Direct Current Journal of Neuroscience. 2009,29(22): 7271-7277.
- Jo JM, Kim YH, Ko MH, Ohn SH, Joen B, Lee KH et al. Enhancing the Working Memory of Stroke Patients Using tDCS. American Journal of Physical Medicine & Rehabilitation. 2009, 88(5): 404-409.
- Boggio PS, Ferrucci R, Rigonatti SP, Covre P, Nitsche M et al. Effects of transcranial direct current stimulation on working memory in patients with Parkinson’s disease. Journal of the Neurological Sciences.2006, 249(1): 31-38.
- Fregni F, Boggio PS, Nitsche M, Bermpohl F, Antal A et al. Anodal transcranial direct current stimulation of prefrontal cortex enhances working memory. Experimental Brain Research. 2005,166(1): 23-30.
- Marshall L, Mölle M, Hallschmid M, Born J. Transcranial direct current stimulation during sleep improves declarative memory. Journal of Neuroscience. 2004,24(44): 9985-9992.
- Batista EK, Klauss J, Fregni F, Nitsche MA, Nakamura-Palacios EM. A Randomized Placebo-‐Controlled Trial of Targeted Prefrontal Cortex Modulation with Bilateral tDCS in Patients with Crack-Cocaine Dependence. Int J Neuropsychopharmacol. 2015, 18(12).
- Conti CL, Moscon JA, Fregni F, Nitsche MA, Nakamura-Palacios EM. Cognitive related electrophysiological changes induced by non-‐ invasive cortical electrical stimulation in crack-‐cocaine addiction. Int JNeuropsychopharmacol. 2014, 17(9): 1465-1475.
- Conti CL, EM Nakamura-Palacios. Bilateral transcranial direct current stimulation over dorsolateral prefrontal cortex changes the drug-cued reactivity in the anterior cingulate cortex of crack-‐cocaine addicts. Brain Stimul. 2014,7(1): 130-132.
- Katayama J, J Polich. Stimulus context determines P3a and P3b. Psychophysiology. 1998, 35(1): 23-33.
- Polich J. Updating P300: an integrative theory of P3a and P3b.Clin Neurophysiol. 2007, 118(10): 2128-2148.
- Franken IH. Two new neurophysiological indices of cocaine craving: evoked brain potentials and cue modulated startle reflex. J Psychopharmacol. 2004,18(4): 544-552.
- Littel M, IH Franken. The effects of prolonged abstinence on the processing of smoking cues: an ERP study among smokers, ex-smokers and never-smokers. JPsychopharmacol. 2007, 21(8): 873-882.
- Namkoong K. Increased P3 amplitudes induced by alcohol-‐related pictures in patients with alcohol dependence. Alcohol Clin Exp Res. 2004,28(9): 1317-1323.
- Volkow ND. Cognitive control of drug craving inhibits brain reward regions in cocaine abusers. Neuroimage. 2010,49(3): 2536-2543.
- Hajcak G. Dorsolateral prefrontal cortex stimulation modulates electrocortical measures of visual attention: evidence from direct bilateral epidural cortical stimulation in treatment-resistant mood disorder. Neuroscience. 2010,170(1): 281-288.
- Meyer BU. Inhibitory and excitatory interhemispheric transfers between motor cortical areas in normal humans and patients with abnormalities of the corpus callosum. Brain. 1995,118(Pt 2): 429-440.
- Chen R. Interactions between inhibitory and excitatory circuits in the human motor Exp Brain Res. 2004,154(1): 1-10.
- Murase N. Influence of interhemispheric interactions on motor function in chronic stroke. Ann Neurol. 2004,55(3): 400-409.
- Fregni F. A sham-controlled trial of a 5-day course of repetitive transcranial magnetic stimulation of the unaffected hemisphere in stroke patients. Stroke. 2006, 37(8): 2115-2122.
- Fregni F. Transcranial direct current stimulation of the unaffected hemisphere in stroke patients. Neuroreport. 2005,16(14): 1551-1555.
- Bajwa S. Impaired interhemispheric interactions in patients with major J Nerv Ment Dis. 2008,196(9): 671-677.
- Knoch D. Disruption of right prefrontal cortex by low-frequency repetitive transcranial magnetic stimulation induces risk-taking behavior. J Neurosci. 2006, 26(24): 6469-6472.
- Fecteau S. Diminishing risk-taking behavior by modulating activity in the prefrontal cortex: a direct current stimulation study. J Neurosci. 2007, 27(46): 12500-12505.
- Bisaga A, P Popik. In search of a new pharmacological treatment for drug and alcohol addiction: N-methyl-D-aspartate (NMDA) antagonists. Drug Alcohol Depend.2000, 59(1): 1-15.
- Addolorato G. How many cravings? Pharmacological aspects of craving treatment in alcohol addiction: a review. Neuropsychobiology. 2005,51(2): 59-66.
- Andrews T. Pharmacological issues in the treatment of concomitant alcoholism and drug abuse. Adv Alcohol Subst Abuse. 1984,3(4): 1-118.
- Reid MS, V Thakkar. Valproate treatment and cocaine cue reactivity in cocaine dependent individuals. Drug Alcohol Depend. 2009,102(1-3): 144-150.
- Diaper AM, FD Law, JK Melichar. Pharmacological strategies for Br J Clin Pharmacol. 2014,77(2): 302-314.