Nicotine, dependence and scientific deception: how Big Tobacco engineered addiction and reinvented risk| Tabaccologia

Abstract

The history of nicotine and tobacco dependence is one of the most emblematic cases of the complex relationship between science, industry and public health. From the chemical discovery of the alkaloid in the nineteenth century, through the gradual understanding of its neuropharmacological and behavioural effects, to the emergence of nicotine dependence as a phenomenon, scientific knowledge has evolved in parallel with industrial strategies to exploit and manipulate this substance. Historical evidence shows that, from the earliest internal research of tobacco companies, nicotine was recognised as the main addictive agent and the key factor in securing consumer loyalty. Yet for more than half a century the industry systematically concealed this information, denying the existence of dependence and spreading artificial uncertainty through a sophisticated apparatus of scientific disinformation. Analysis of internal documents, now accessible thanks to the Legacy Tobacco DocumentsLibrary, has made it possible to reconstruct beyond doubt the strategy of scientific deception adopted by Big Tobacco: a strategy first based on risk denial, then on the manufacture of doubt and, more recently, on the rhetoric of harm reduction. In each of these phases, science was bent to instrumental use, transformed from a tool of knowledge into a means of commercial legitimisation. Modern market innovations – electronic cigarettes, heated tobacco products and synthetic nicotine – show that the industry continues to apply the same paradigm, updating the language while maintaining its primary goal: preserving dependence and normalising nicotine consumption. The “harm reduction” narrative, though based on elements of partial truth, risks undermining decades of progress in tobacco control and re-creating new forms of dependence among younger generations. From this perspective, the story of nicotine and Big Tobacco’s deception takes on paradigmatic value. It shows that scientific truth, in order to be truly effective in public health, must be accompanied by transparency, independence and ethical responsibility. Only science free from economic interference and grounded in principles of integrity can prevent similar distortions from recurring. Finally, the experience gained in confronting the tobacco industry offers a universal lesson: the protection of collective health depends not only on the accumulation of scientific evidence but also on the ability of institutions and the scientific community to defend truth against manipulation by economic power. In an era marked by new forms of disinformation and dependence, this lesson remains more relevant than ever.

Introduction

Nicotine is an alkaloid found mainly in the leaves of Nicotiana tabacum, where it reaches high concentrations (typically 10–20 mg per gram of dried tobacco). During the combustion of the tobacco product (which, during inhalation, occurs at temperatures of about 800–900 °C), the amount of nicotine transferred into the smoke that is inhaled can vary approximately from 1 to 10 mg per cigarette. One gram of dry tobacco contains a total of about 15–25 mg of alkaloids, of which nicotine accounts for around 90%; the remaining fraction is made up of other alkaloids such as nornicotine, anabasine, anatabine, myosmine, 2,3-bipyridine, etc. [1,2].

From a toxicological point of view, nicotine is a fast-acting and highly toxic substance, known for its neurotoxic properties. Among natural poisons, nicotine is one of the most powerful: relatively small doses of pure nicotine can be lethal, and there are historical accounts of its use as an intentional lethal agent. In experimental models, a small amount of oily extract of tobacco leaves instilled into a dog’s eye has in some cases produced fatal outcomes within minutes, a phenomenon that also reflects the defensive role of this alkaloid against predators and parasites of the plant. Historically used as a pesticide, nicotine inspired the synthesis of neonicotinoids, a class of insecticides widely employed in agriculture that have recently been linked to the die-off of bees, bumblebees and other pollinating insects. An increase in accidental poisoning episodes has also been observed in connection with the spread of vaping and the commercial availability of e-liquids for electronic cigarettes containing high concentrations of nicotine [3].

The chemical discovery of nicotine

The history of nicotine goes back more than two centuries. In 1559 Jean Nicot introduced tobacco at the court of the King of France, describing it as a medicinal plant and recommending its use to relieve Queen Catherine de’ Medici’s migraines. The alkaloid was later isolated for the first time from tobacco leaves in 1809 by the French chemist Louis-Nicolas Vauquelin, who named it “nicotine” in honour of Jean Nicot. In 1828, Posselt and Reimann of the University of Heidelberg isolated and purified nicotine, identifying it for the first time as the main alkaloid contained in tobacco. In 1843 Melsens determined its empirical molecular formula (C₁₀H₁₄N₂), while Schloesing, in 1847, calculated its molecular weight (162.23 g·mol^-1). In 1895 Adolf Pinner definitively clarified its chemical structure, establishing the molecular conformation that we know today. The first chemical synthesis of nicotine was achieved in 1904 by Amé Pictet and Alois Rotschy. Studies on the metabolism of the substance began in the 1950s. Subsequently, in 1981 and 2000, the first enantioselective syntheses (designed to selectively produce one of the two mirror-image forms, or enantiomers, of the molecule) of the two optical forms of natural nicotine were obtained: (S)-nicotine and (R)-nicotine [4–5].

At the origins of dependence: history and neurobiology of nicotine

Tobacco smoking, that is, dependence on tobacco consumption, is an ancient phenomenon. The first historical evidence of a condition comparable to nicotine dependence is found in accounts by Bartolomé de Las Casas (Seville, 1474/1484 – Madrid, 1566), missionary and chronicler of the West Indies, who witnessed Christopher Columbus’s fourth voyage [6–8]. Las Casas’s observations constitute the first documented description of behaviour compatible with the development of nicotine dependence: “Men with a firebrand in their hands and certain herbs... which are dry herbs wrapped in another leaf, also dry, in the form of a tapered cylinder, lit at one end... when reproached for this disgusting habit, they replied that they found it impossible to stop.”

In fact, despite such admonitions, the use of tobacco quickly spread among the missionaries.

From a neurobiological standpoint, nicotine is the main psychoactive agent in tobacco. After inhalation, it reaches the central nervous system in about 8–10 seconds, binding to nicotinic cholinergic receptors located in various brain areas. Activation of receptors in the nucleus accumbens triggers the release of dopamine, responsible for feelings of reward and pleasure; in the locus coeruleus, the release of noradrenaline increases alertness and cognitive performance; finally, modulation of serotonin influences hypothalamic centres of appetite and mood.

Nicotine is considered the primary substance responsible for the development of dependence [9–15]. Although tobacco smoke contains numerous toxic compounds (tar, carbon monoxide, acetaldehyde, nitrosamines, etc.), only nicotine has pharmacological properties capable of inducing self-administration and drug-seeking behaviours similar to those observed with other drugs of abuse [15–20]. The effects of nicotine are dose-dependent and include both rewarding responses (euphoria, relaxation) and adverse ones (nausea, dizziness), modulated by individual sensitivity and degree of tolerance [21]. Nicotine dependence reflects the integration of contrasting signals from different brain circuits involved in reward and aversion. As with other drugs, interruption of intake causes a withdrawal syndrome characterised by irritability, anxiety, insomnia, difficulty concentrating, increased appetite and intense craving [18,21].

Chronic exposure to nicotine induces desensitisation of nicotinic receptors, followed by a compensatory up-regulation mechanism with an increase in receptor density on the neuronal membrane, whereas prolonged abstinence allows a gradual return to baseline receptor levels [22–24]. However, although these mechanisms are reversible, smoking cessation remains difficult in many cases. The reasons include not only neurochemical adaptation but also psychological and environmental factors.

Cues associated with smoking behaviour – places, rituals, smells and social interactions – act as conditioned stimuli that reinforce the behaviour and make its extinction complex. Craving can persist for years after quitting [25].

Tobacco dependence is classified as a chronic relapsing disease [26], sustained by a twofold component: a physical component, related to neurochemical dependence on nicotine, and a psycho-behavioural component, related to motivational and environmental aspects [27,28]. Tobacco use meets the criteria defined by the World Health Organization and other international agencies (CDC, FDA, DSM-5) for the diagnosis of substance use disorder [29,30].

Nicotine is therefore the main psychotropic substance in tobacco, responsible for the onset and maintenance of dependence. The scientific literature has debated whether the term “tobacco dependence” or “nicotine dependence” is more appropriate. Fagerström – the creator of the eponymous test for assessing dependence – proposes the term tobacco dependence, emphasising the psycho-environmental complexity of the act of smoking, which goes beyond the pharmacological effect of nicotine alone [31]. However, the current spread of nicotine-containing products (electronic cigarettes, heated tobacco devices, oral pouches, etc.) confirms that nicotine itself is a strongly addictive agent, capable of inducing dependence even in the absence of tobacco combustion, especially in young people.

Awareness and concealment: how the tobacco industry internally managed nicotine dependence

Tobacco multinationals (collectively known as Big Tobacco) long publicly denied that nicotine was an addictive substance, supporting this position even under oath in front of United States Congress. For more than fifty years, the leading companies maintained a tacit agreement to preserve a common stance of denial and to conceal available scientific data, until the late 1990s, when former executive Jeffrey Wigand of Brown & Williamson Tobacco Corporation made public confidential information documenting the companies’ internal knowledge of the neurobiological and dependence-producing effects of nicotine [32].

In reality, already in the early 1990s – prior to Wigand’s testimony – confidential documents belonging to Brown & Williamson Tobacco Corporation (B&W) and its parent company British American Tobacco Company (BAT) had been anonymously submitted to the U.S. Congress by a former BAT official. Although not admissible as evidence in court, these materials included confidential reports on internal research regarding nicotine, as well as numerous internal memoranda exchanged among researchers, executives and legal consultants of the industry [33].

In 1998 the Tobacco Master Settlement Agreement (MSA) was signed, an agreement between 46 U.S. states and the four major American tobacco companies which, by bringing to an end lawsuits seeking reimbursement for health-care costs related to smoking, led the multinationals to accept advertising restrictions, to make permanent annual payments to states to compensate for smoking-related health expenditures, and to agree to publish their internal documents classified as confidential and top secret (up to 2021).

Important documents thus became declassified and publicly available, collected in specially created archives accessible to all. The Legacy Tobacco Documents Library (LTDL), established in 2002 at the University of California, San Francisco, is the most comprehensive documentary source for this evidence. Following extensive cataloguing, it has gathered more than 13 million corporate documents, corresponding to about 80 million pages, from the main tobacco multinationals. A search in the database for the term “nicotine” yields more than two million documents – memoranda, technical reports and internal communications – showing that the tobacco industry was fully aware of the pharmacological properties of nicotine and its central role in the development and maintenance of tobacco dependence [34–36].

Thanks to the disclosure of confidential corporate documents [32–36], it has emerged that for more than twenty-two years (from 1962 to 1984), researchers and executives of Brown & Williamson Tobacco Corporation (B&W) and British American Tobacco Company (BAT) conducted extensive studies on nicotine and achieved a detailed, scientifically accurate understanding of the pharmacology of this substance. These documents clearly show that:

1. nicotine is the main pharmacological agent responsible for dependence;
2. inhalation of smoke is an essential condition for the optimal absorption of the active substance;
3. nicotine dependence drives smokers to maintain sufficient consumption, in both duration and intensity, to cause, over the long term, serious diseases and premature mortality [35–38].

In particular, in 1963 scientists and executives of the two companies openly admitted that nicotine induced dependence. In a memorandum dated 17 July 1963, senior executive Addison Yeaman stated: “Nicotine is addictive; we are in the business of selling nicotine, an addictive drug effective in the relief of stress mechanisms.”

In those same years, public debate on the harmfulness of tobacco smoke intensified following the first official report of the British Royal College of Physicians (RCP) on tobacco and health [39], which was followed by the 1964 U.S. Surgeon General’s Report (the Terry Report) [40,41]. The RCP document concluded that cigarette smoking was a primary cause of lung cancer and recommended that the British government adopt decisive measures to address the problem.

At the same time, in 1962 BAT entered into a research contract with the Battelle Memorial Institute (a renowned research centre still active today, based in Columbus, Ohio, USA), known as Project Hippo I, to systematically study the physiological and behavioural effects of nicotine. The goal was not to protect health, but to gain a deeper understanding of how nicotine acted on the brain, especially in areas that regulate stress, weight control and hormonal balance, in order to optimise the “satisfaction” of smoking and keep consumers dependent [42].

In addition to Projects Hippo I and Hippo II, Battelle conducted systematic studies on the pharmacokinetics of nicotine, analysing its absorption, distribution and elimination. It was shown that inhalation was the most efficient route for absorption of the substance [43]. Using carbon-14-labelled nicotine, researchers measured the amount of nicotine absorbed by different groups of smokers: “non-inhaling” subjects absorbed between 22% and 42% of the dose, while regular inhalers reached values between 70% and 90%. Those who expelled the smoke quickly after inhaling had intermediate absorption between 40% and 50% [33].

Taken together, the declassified documents demonstrate that between 1962 and 1984 B&W and BAT carried out a broad research programme aimed at understanding and exploiting the neurobiological effects and dependence potential of nicotine. This evidence shows that the companies fully recognised the addictive nature of the substance, considered its fundamental role in maintaining tobacco consumption and intended to influence consumer behaviour by modulating the effects of nicotine [33].

Indeed, in a context of increasing profit maximisation, even at the expense of consumer safety, the tobacco companies went further, pursuing strategies aimed at enhancing the penetration and efficacy of nicotine in commercial products. This approach would find its most systematic development in the research and innovations later introduced by Philip Morris Inernational Inc. (PMI).

Philip Morris Inernational Inc.

A confidential internal document from PMI reveals that the main tobacco multinationals were perfectly aware of the dual mechanism of dependence induced by smoking: a chemical dependence due to the pharmacological action of nicotine, and a psycho-behavioural dependence linked to the rituals, contexts and sensory and social associations that accompany the act of smoking. These concepts were set out in an internal report entitled “Motives and Incentives in Cigarette Smoking,” drafted by Dr William L. Dunn Jr, a psychologist hired as a researcher by PMI in 1961 [43]. The document, intended for internal circulation only, was written following Dunn’s participation in a conference on “Why People Smoke Cigarettes?” held on the island of St. Martin (Caribbean) in 1972, organised by the Council for Tobacco Research (CTR) – a body created by the tobacco industry with the aim of countering, through the production of scientific counter-narratives, the growing evidence on the harmful effects of smoking.

In his report, Dunn systematically analysed the psychological motivations underlying smoking behaviour, identifying various categories of incentives:

1. search for social acceptance and self-esteem;
2. sensory pleasure;
3. oral gratification (in the psychoanalytic sense);
4. psychomotor relaxation and reduction of bodily tensions;
5. pharmacological effects of smoke, mainly attributed to nicotine.

Dunn described the so-called “paradox of smoking,” namely the cigarette’s ability to produce calming and stimulating effects at the same time, and identified nicotine as the main cause of this phenomenon. In the text he wrote: “Without nicotine there would be no smoking.” To support this statement, he reported three key observations:

1. no one becomes a smoker by consuming nicotine-free cigarettes;
2. the physiological effects of smoking are directly nicotine-dependent;
3. the tobacco industry sets an average nicotine content of about 1 mg per cigarette, because lower concentrations reduce smoker satisfaction and, consequently, sales.

Dunn then asked why there was no stand-alone market for nicotine itself, hypothesising that it could be “eaten, sucked, drunk, injected or inhaled as an aerosol.” The answer, in his view, lay in the delivery form of the product: the cigarette should not be considered a simple commercial item, but a perfectly designed drug-delivery device.

The pack, Dunn wrote, is a portable, immediately accessible container; the cigarette, in turn, is the optimal nicotine dispenser, able to automatically regulate the inhaled dose according to depth and frequency of puffs, while avoiding toxic levels. The inhalation route, highly efficient (absorption up to 97%), allows rapid entry into the systemic circulation within 1–3 minutes, without pain or invasiveness. These features make the cigarette “the ideal vehicle for nicotine delivery.”

Although aware that he was describing a model comparable to the administration of a drug of abuse, Dunn sought to normalise the concept by comparing it with other everyday examples: glasses as devices for delivering alcohol, cups for delivering caffeine or matches for lighting fires. However, he lucidly recognised that his analysis answered not so much the question “Why do people smoke?” as “Why do smokers take nicotine?”

Later in the report, Dunn further examined the motivational and behavioural aspects of smoking, drawing on the work of Clark Hull, another American psychologist funded by the tobacco industry. In particular, he analysed:

1. differences between smokers and non-smokers;
2. physiological responses of the human body to inhalation of smoke;
3. behavioural and environmental variables associated with the formation of the smoking habit [43].

Dunn acknowledged that, although the primary incentive to smoke derives from the pharmacological effects of nicotine, secondary reinforcers emerge over time as smoking becomes integrated into daily lifestyle. Just as eating behaviour may involve eating for pleasure and not for hunger, smoking can be maintained in the absence of physiological need, through conditioned mechanisms, behavioural rituals, sensory preferences and social norms that consolidate the habit.

Reading the document clearly shows that, already in the 1960s and 1970s, Philip Morris possessed detailed knowledge of both the pharmacological effects of nicotine and the psycho-behavioural dynamics of dependence. Dr Dunn – internally nicknamed “Nicotine Kid” – was among the first industry researchers to describe chemical nicotine dependence accurately while recognising its behavioural component. His observations anticipated many of the conclusions that the scientific community would only reach decades later [43].

The chemical engineering of nicotine dependence and ammonia: Big Tobacco’s industrial secret

In the 1960s the Winston brand of cigarettes, produced by R.J. Reynolds Tobacco Company (RJR), held a market share three times that of Marlboro, a brand owned by Philip Morris – then the smallest of the six leading U.S. manufacturers. However, starting in 1968 Marlboro became the world’s best-selling brand: one in five cigarettes smoked was a Marlboro, and more than 50% of its consumers were under 17 years old. This extraordinary growth caused great concern among competitors and led RJR to conduct an in-depth chemical analysis of Marlboro cigarettes to understand their “competitive advantage.”

The investigations revealed that PMI had introduced an apparently marginal but highly impactful technological innovation: the controlled addition of ammonia to tobacco. This “ammonia technology” intentionally modified the chemistry of smoke, raising the pH of the final product. Marlboro cigarettes had a pH between 6.8 and 7.3, compared with an average value of 5.8–6.0 in Winston. Increasing alkalinity favoured the conversion of nicotine from its protonated (ionic) form to the free-base form, which is more volatile and more rapidly absorbed in the lungs [44,45]. This free-base nicotine is responsible for the so-called “kick,” the immediate pleasurable sensation and acute psychoactive effect that accompanies the first puffs. In pharmacokinetic terms, ammoniation ensured almost complete absorption of inhaled nicotine (≈100%), compared with 50–60% in untreated cigarettes. This technique, also known as nicotine “free-basing,” made cigarettes more potent and quickly rewarding, increasing their addictive potential and deceiving consumers [46,47].

a) Technological origin of the process

In the 1950s PMI began using reconstituted tobacco sheets (reconstituted tobacco or recon) to recover waste such as stems and midribs from leaves. To obtain a smokable material and improve the mechanical strength of the sheets, diammonium phosphate (DAP) was used, a salt capable of releasing pectins and forming an adhesive gel useful for assembly, as well as improving aroma. In 1961 PMI scientists discovered that, in addition to its technological functions, DAP also acted as a “releasing” agent for nicotine, increasing the free-base fraction. The company patented the process in 1967, but in the patent omitted any reference to effects on nicotine bioavailability, limiting itself to describing the structural and aromatic properties of the material [48–54]. In the 1990s PMI publicly claimed that ammonia was used solely to “improve flavour” or “reduce nicotine content,” denying that it could increase the amount of nicotine delivered to the smoker’s brain. However, analysis of confidential industry documents shows that ammoniation of nicotine was long one of the main research priorities of the tobacco multinationals [55–57].

b) Chemical mechanism and physiological purpose

Internal reports reveal detailed knowledge of three key aspects:

1. Nicotine exists in different chemical forms: as a salt in the particulate phase of smoke and as free nicotine in both the particulate and vapour phases.
2. Free nicotine in the vapour phase is pharmacologically active because it rapidly crosses the alveolar–capillary barrier, reaches the brain in a few seconds and induces an intense reinforcing and rewarding effect (hit effect or “strong impact,” “kick”); the speed at which nicotine is delivered is a key aspect of dependence and the reason why nicotine gums and patches generally do not provide the same satisfaction as smoking [58–62].
3. Ammoniation, that is, adding ammonia to tobacco to increase smoke pH, promotes the transition of nicotine to the free-base form (as happens with cocaine when it is “cracked”). As stated in an internal RJR document from 1973: “Even with an old-style filter, by adjusting pH one can get any additional ‘kick’ desired.” To avoid associations with crack cocaine (also obtained through a free-basing process), companies carefully removed the term “free-based” from official documents [63–66].

c) Industrial and commercial implications

Once the link between pH, free nicotine and sensory impact was understood, ammoniation became a strategic industrial research objective. PMI, a pioneer of the process, began using ammonia in 1965 and gradually increased its use until 1974 – a period that coincided with the exponential growth in Marlboro sales. Chemical “reverse engineering” analysis of Marlboro cigarettes carried out by competitors led to the conclusion that ammonia technology was “the secret and soul of Marlboro” [67–70].

Although no company publicly admitted it, almost all multinationals—with the exception of Liggett Group – adopted the same procedure, referring to it internally as “improving customer satisfaction” [71–74].

In the 1970s, as public concern grew about the health effects of smoking and demand for “low-tar” cigarettes increased, companies faced a dilemma: how to reduce tar without reducing nicotine, so as not to compromise consumer dependence. As BAT chemist Green wrote in 1976: “If nicotine delivery falls below the threshold of satisfaction, smokers will ask themselves why maintain such an expensive habit” [75].

The free-basing methodology offered the solution: reducing total levels of tar and nicotine while maintaining – or even increasing – the amount of free nicotine through ammonia [76,77]. Technical conferences dedicated to “ammonia technology” were even organised to promote rapid commercial application and harmonise research strategies [68]. Ammoniation of nicotine nevertheless remained an “industrial secret” until the late 1990s.

d) Genetic engineering of tobacco

At the same time, fearing that public health authorities might push for a ban on ammonia use, the multinationals began exploring genetic approaches to increase the natural nicotine content of tobacco. High-nicotine tobacco would make “more free nicotine available to the smoker” [75,78].

In 1977 new varieties of Virginia tobacco, called Y-1, were developed with a nicotine concentration double the standard. Subsequently, the biotechnology company DNAP transferred Y-1 genes to Burley tobacco, achieving a 50–75% increase in leaf nicotine. To offset the deterioration in flavour associated with these modifications, companies adopted an “expansion process” of the cut filler that transformed it into flakes—similar to the production of puffed rice. This process, already used by the tobacco industry to save money by selling consumers “more air and fewer leaves,” was applied here as well to reduce tobacco density and improve sensory experience [75,78].

In summary, documentary evidence shows that the tobacco multinationals were not only fully aware of nicotine’s addictive power, but deliberately acted to enhance it, resorting to chemical ammoniation processes and even genetic manipulation of plants. Yet despite all this, in 1994 the heads of the leading companies testified before the U.S. Congress uttering the famous phrase: “No, sir, nicotine is not addictive”!

A scientific and moral deception lasting more than fifty years—a “perfect crime,” in which dependence was not only known but engineered.

The tobacco industry, early dependence and additives: an attack on new generations

By manipulating cigarette smoke chemistry, the tobacco industry succeeded in inducing subtle but significant neurochemical changes in smokers’ brains, favouring the development of earlier and more intense nicotine dependence. This strategy had a particular impact among adolescents, leading to a marked increase in the prevalence of regular smokers in younger age groups compared with previous generations [79]. Once made public, internal company documents proved that commercial interest in the youth market was explicit and systematic. In a confidential R.J. Reynolds memorandum entitled “The Concept of a Cigarette to Ensure RJR a Larger Share of the Youth Market,” the goal is clearly stated of “capturing and retaining” younger smokers, recognising the adolescent target as a strategic resource for the future sustainability of the market [79].

a) Additives

In parallel, the multinationals adopted a range of technological and sensory additives with three main aims [64]:

1. To facilitate smoking initiation by improving the taste of tobacco and making the cigarette more pleasant, attractive and “socially acceptable.”
2. To favour maintenance of consumption by reducing oropharyngeal irritation and increasing tolerability even in inexperienced smokers.
3. To mask the smell and visibility of environmental tobacco smoke, reducing risk perception and social stigmatisation associated with passive smoking, without lowering its toxicity.

In the European context, more than 600 additives have been used in tobacco processing, regulated by fragmented legislation lacking strict toxicological standards [80]. Among the most widely used additives are sweeteners, liquorice and chocolate, used to attenuate bitter taste and facilitate sensory acceptance by young people or novice smokers. Menthol, thanks to its local anaesthetic properties, reduces the perception of irritation and burning, favouring deeper inhalation. Cocoa is used to dilate airways, allowing greater penetration of smoke and thus more extensive absorption of nicotine and tar in the lungs. It has also been shown that many of these additives – including sweeteners, liquorice, guar gum, humectants and colourants such as tartrazine – undergo chemical transformations during combustion that generate carcinogenic or respiratory-toxic compounds [64,67]. In this way, products designed to increase palatability and reduce risk perception have paradoxically contributed to amplifying exposure to harmful substances and strengthening dependence mechanisms, especially among young people.

b) Menthol and synthetic derivatives: sensory modulation and enhancement of nicotine dependence

In February 2014 the European Union adopted a directive requiring the progressive removal of additives from tobacco products starting in 2016 [81]. However, under industry pressure, menthol was granted a derogation until 20 May 2020, despite its known role in facilitating the development of nicotine dependence [82].

Menthol is a chiral alcohol with refreshing, analgesic and mildly irritating sensory properties. Beyond its organoleptic effects, it exerts significant actions on the respiratory system, the central nervous system and hepatic nicotine metabolism, contributing to increased addictive potential [83,84]. Its activity is mediated by the TRPM8 (Transient Receptor Potential Melastatin 8) receptor, present along the airways and on trigeminal endings in the nose and mouth [85]. Activation of TRPM8 generates an influx of Ca²⁺ and K⁺ ions that produces the typical “cooling” sensation, attenuating the perception of irritation and suppressing the cough reflex. In this way, menthol makes smoke more pleasant and easier to inhale and favours initiation of smoking, especially among novices.

At the bronchial level, menthol induces mucus hypersecretion and production of pro-inflammatory interleukins (IL-13, IL-25, IL-33), increases expression of the anti-apoptotic factor Bcl-2, inhibits metabolism of the carcinogen NNAL and amplifies the TRPM8-mediated inflammatory response, worsening bronchoconstriction in people with COPD [86,87]. Similar mechanisms are observed in e-liquids for electronic cigarettes and heated tobacco products, where menthol contributes to comparable respiratory damage [88]. In the liver, menthol inhibits cytochrome CYP2A6, responsible for nicotine metabolism, leading to prolonged presence of the substance in the blood and extending its bioavailability [84]. In addition, it alters the function of α4β2 and α6β2 nicotinic receptors in the nucleus accumbens and ventral tegmental area, enhancing dopamine release and making cessation more difficult [83,89].

Despite its ban in Europe and North America, the tobacco industry has circumvented regulations by replacing menthol with chemically related synthetic cooling compounds (“replicants”) that are not yet regulated. One example is WS-3, an odourless cooling agent with a structure similar to menthol, introduced by R.J. Reynolds to achieve the same sensory effect and maintain product appeal in the absence of robust safety data [90].

Scientific deception and the manufacture of doubt

From the 1960s onwards, the leading tobacco multinationals implemented a systematic communication and disinformation strategy aimed at minimising emerging scientific evidence on the harmful effects of smoking. This strategy, now described in the literature as manufacturing doubt, was designed to shift the debate from scientific certainty to alleged controversy, with the goal of delaying the adoption of regulatory measures and maintaining consumer confidence. As early as 1953, following the publication of epidemiological studies linking cigarette smoking to lung cancer (including those by Doll and Hill and by Wynder and Graham), manufacturers met in a secret meeting at the Plaza Hotel in New York. From this meeting the Tobacco Industry Research Committee (TIRC) was born, later renamed the Council for Tobacco Research (CTR). Officially established to promote “independent research” on health and smoking, the CTR was in fact conceived as a public-relations instrument to create the appearance of scientific commitment, while its real function was to sow uncertainty and neutralise unfavourable conclusions [91,92].

Through the CTR and their own internal laboratories, the companies funded studies designed to delegitimise epidemiological evidence and to emphasise the idea that smoking might be a “personal” risk behaviour rather than a direct cause of disease. At the same time, academic consultants and communication agencies were hired to spread messages aimed at weakening the credibility of independent research. In this way, Big Tobacco succeeded for decades in maintaining an “institutionalised scientific doubt,” functional to protecting its market. One of the most emblematic internal documents is the 1969 Brown & Williamson memorandum “Doubt is our product” [93], which explicitly states: “Doubt is our product, since it is the best means of competing with the ‘body of fact’ that exists in the mind of the general public. It is also the means of establishing a controversy.”

This approach, later extensively documented in the Legacy Tobacco Documents Library, shows how the deliberate creation of scientific ambiguity was a planned and conscious strategy. The aim was not to refute science but to distort the perception of uncertainty: it was enough to insinuate that the evidence was not “conclusive” to keep consumption stable and delay health regulation [93]. From a historical-epistemological perspective, Big Tobacco’s strategy represents one of the first structured examples of corporate denialism, in which the production of scientific knowledge is bent to marketing purposes. This model – based on selective funding, manipulation of results and strategic use of public communication – became a paradigm later replicated by other industries, from alcohol to fossil fuels and ultra-processed foods.

The “scientific deception” orchestrated by Big Tobacco has had far-reaching consequences for global public health. The delay in political and social recognition of the dangers of smoking [94,95] contributed to millions of preventable deaths and slowed the implementation of preventive measures such as product labelling, educational campaigns and advertising restrictions. Moreover, the strategy of manufacturing doubt had a lasting impact on public trust in science, creating a precedent for erosion of scientific credibility that continues to influence debates on other health and environmental issues. Analysis of the tobacco industry’s historical documents shows that scientific deception was not a side effect but a structural element of Big Tobacco’s industrial policy. The creation of pseudo-scientific entities, the recruitment of experts to disseminate “alternative” opinions, data manipulation and ambiguous communication formed a coordinated long-term strategy. From a contemporary perspective, this story is a key case study for understanding the relationship between science, economic power and public health. It underscores the importance of transparency in scientific research, independence of funding and ethical communication of evidence as fundamental tools to prevent similar distortions in today’s scientific debate.

From scientific deception to tobacco regulation

The progressive unmasking of the tobacco industry’s disinformation strategies – made possible by investigative journalism, civil trials and the publication of confidential company documents – marked a turning point in the history of modern public health. Starting in the 1970s, the growing body of epidemiological and toxicological evidence compelled health authorities to reassess the role of smoking as a primary determinant of disease and mortality.

a) The first reactions of the scientific community

In 1964 the publication of the U.S. Surgeon General’s Report (Smoking and Health: Report of the Advisory Committee to the Surgeon General) represented the first official governmental acknowledgment of the causal link between smoking and lung cancer. This was followed in 1971 by the Royal College of Physicians (RCP) Report in the United Kingdom, which laid the scientific foundations for the first policies to reduce tobacco consumption and recommended advertising restrictions, health warnings on packaging and public education programmes [39,40].

These documents marked the transition from a phase of manipulated uncertainty to one of consolidated scientific awareness. At the same time, psychopharmacology and neuroscience studies confirmed the role of nicotine as an addictive agent, cementing the view of smoking as a chronic relapsing disease rather than a simple behavioural habit [96].

From the 1980s on, the World Health Organization (WHO) and major international health institutions adopted a global approach to tobacco control, based on three fundamental pillars:

1. Primary prevention through educational campaigns and awareness-raising;
2. Market regulation via advertising restrictions, product taxation and smoking bans in public places;
3. Treatment of dependence through clinical and pharmacological cessation programmes.

The culmination of this process was the signing in 2003 of the Framework Convention on Tobacco Control (FCTC), the first international public health treaty adopted by WHO. Entering into force in 2005, the FCTC established a binding legal framework for reducing the demand for and supply of tobacco products, introducing measures such as price increases, comprehensive advertising bans, protection from second-hand smoke and action against illicit trade [97].

b) The role of evidence and scientific transparency

The construction of tobacco-control policies was based on a progressive reappropriation of science by public institutions. Independent studies funded by governmental and academic bodies made it possible to overcome the information dominance exercised by Big Tobacco. Furthermore, the online publication of the Legacy Tobacco Documents Library (LTDL) in 2002 enabled, for the first time, public and transparent access to millions of corporate documents, providing a fundamental resource for research and evidence-based policymaking [34]. This process marked the birth of a new culture of scientific and institutional responsibility, in which the production of evidence and its communication to the public became essential tools for protecting collective health.

The evolution of the institutional response to smoking shows how scientific transparency, international cooperation and the legitimisation of evidence are indispensable elements in countering industrial practices of information manipulation. The experience of tobacco control is a paradigmatic example of how science can again become a public good, capable of guiding global policies based on evidence rather than economic interest.

In addition, the experience gained in confronting the tobacco industry has provided conceptual and regulatory tools now applied in other fields – from environmental policy to combating obesity and behavioural addictions – confirming that fighting industrial disinformation is an integral part of promoting global health.

The contemporary evolution of the tobacco industry: new forms of scientific deception

In the past two decades, tobacco companies have faced a progressive decline in global consumption of traditional cigarettes, a direct result of control policies, taxation, reduced advertising and increased awareness of health risks. In response, Big Tobacco has implemented a strategy of commercial and narrative repositioning aimed at maintaining profitability through promoting new nicotine-delivery technologies, such as:

1. electronic cigarettes (e-cigarettes);
2. heated tobacco products (HTPs);
3. oral nicotine systems (nicotine pouches, lozenges and sublingual sprays);
4. synthetic nicotine not derived from plants [98–100].

a) From denial of harm to the concept of harm reduction

The main rhetorical shift introduced by the industry has been moving from denial of harm to a narrative of harm reduction. Companies claim that these products are “safer” alternatives to conventional cigarettes because they eliminate or reduce combustion, the main source of toxic substances. However, numerous independent analyses have shown that this claim is highly questionable: although certain carcinogenic compounds are indeed reduced in these new products compared with cigarettes, others are clearly present in these devices and absent or present only in low concentrations in conventional cigarettes. Moreover, exposure to nicotine, aldehydes, heavy metals and ultrafine particulate remains significant, and the long-term effects on cardiovascular and respiratory health are still under investigation [101–103].

This new communication strategy reproduces, in updated form, Big Tobacco’s historic logic: reinterpreting scientific uncertainty as a marketing tool. The concept of harm reduction is often used selectively, with favourable data highlighted and unfavourable data omitted or minimised. Without rigorous methodological transparency, this approach risks undermining tobacco-control policies and renormalising nicotine use among young people.

b) The case of electronic cigarettes and heated tobacco products

With the launch of the IQOS device, PMI International (PMI) was the first multinational to introduce the concept of the heated tobacco product on a global scale, presenting it as a “scientifically validated alternative” to cigarettes. However, independent studies have revealed that aerosols produced by these devices contain numerous toxic substances, including tobacco-specific nitrosamines (TSNAs) and volatile organic compounds, albeit at lower concentrations than in conventional smoke [104,105]. Moreover, the high efficiency of nicotine delivery and the speed with which it reaches the central nervous system keep the addictive potential essentially unchanged, similar to that of conventional cigarettes.

Electronic cigarettes, introduced to the market from 2006 onwards, represent an even more complex case. Although initially marketed as smoking-cessation tools, numerous epidemiological studies have shown predominant use among adolescents and young adults who were previously non-smokers, thereby creating a new risk of nicotine initiation [106-108]. The diversity of devices, variability of nicotine concentrations and presence of attractive flavours (fruity, sweet, mentholated) contribute to a perception of “harmlessness,” reinforced by targeted marketing and promotion via social media.

c) The rebirth of nicotine marketing

The current historical phase shows how multinationals have managed to reinvent the nicotine product through new technological and narrative platforms. The goal is no longer to deny dependence, but to redefine it as a manageable behaviour, even compatible with a “modern,” “controlled” lifestyle. In this way, the industry proposes a new form of normalised dependence, scientifically packaged as harm reduction yet essentially aimed at maintaining the nicotine market. The dynamics observed in today’s tobacco industry reveal a structural continuity with the scientific deception of the past. Whereas in the twentieth century the strategy was based on denying harm, today it relies on selective management of evidence, using science not to protect public health but to legitimise new consumption models.

The historical experience of tobacco suggests that every technological innovation introduced by the industry must be evaluated with independent rigour, outside corporate narratives. Without such vigilance, new nicotine-delivery forms risk perpetuating, with more sophisticated language, the same scientific deception that has characterised the industry for over half a century.

Public-health and bioethical implications

The emergence of new nicotine-delivery platforms – electronic cigarettes, heated tobacco products and synthetic nicotine – has reopened a complex debate on the scientific, regulatory and ethical responsibilities of the various stakeholders: industry, scientific community, health institutions and public opinion. The ways in which Big Tobacco has reinterpreted science and the language of harm reduction today raise issues that go beyond toxicology and pharmacology, touching the very foundations of research ethics and health justice.

a) The risk of re-normalising nicotine use

One of the main threats to public health is the social re-normalisation of nicotine use, fuelled by the widespread perception – largely induced by marketing – that new devices are “less harmful” or even “safe.” Numerous studies indicate that e-cigarette use among adolescents and young adults significantly increases the likelihood of transitioning to combusted smoking within a few years [109,110]. This phenomenon, known as the gateway effect, reintroduces nicotine as a common substance of use, reversing decades of progress achieved by tobacco-control policies. From an ethical perspective, the industrial strategy of promoting potentially harmful products using narratives of personal freedom or “controlled well-being” amounts to a form of cognitive manipulation of consumers’ informed consent, in conflict with the principles of autonomy and transparency that should govern health communication.

b) Conflict of interest and scientific research

Collaboration between universities, regulatory agencies and the tobacco or nicotine industry poses another ethical dilemma. Although private funding for research represents an important economic resource, historical experience shows that financial dependence on the funding source can distort the formulation of scientific questions, the selection of data and their interpretation [111]. Meta-research studies have demonstrated that research sponsored by tobacco or e-cigarette companies is more likely to report favourable results for their products than independent studies, confirming the presence of a systematic bias of economic origin [112,113]. In this context, the principle of research integrity requires full transparency in declaring conflicts of interest, adoption of open-data systems and promotion of independent public funding for public-health research.

c) Protection of minors and collective responsibility

Another critical aspect concerns the protection of vulnerable populations, particularly minors and young adults, who today represent the main marketing target for new nicotine products [114]. The availability of attractive flavours, the eye-catching design of devices and promotion through social media constitute a form of indirect advertising that circumvents regulatory restrictions and encourages early initiation. From a bioethical standpoint, this strategy violates the principle of non-maleficence – “first, do no harm” – because it exposes vulnerable groups to substances potentially harmful to neurocognitive development and to a long-term risk of dependence.

d) Towards an ethics of scientific responsibility

The current situation compels us to rethink the responsibilities of the scientific community. The history of the tobacco industry shows that the production of knowledge can have powerful social consequences. Today, scientific disinformation is also used for economic interests, so researchers must not only produce data but also safeguard the quality of research and communicate results correctly to the public. For research on nicotine dependence, this means adhering to three key principles:

1. maximum transparency about funding sources and data;
2. independence from commercial interests;
3. responsibility in communicating with citizens, especially the youngest.

The new nicotine industry shows that public health and bioethics must work together. Fighting disinformation and conflicts of interest in the field of tobacco is an ethical as well as a scientific issue. Only an integrated approach – based on rigour, transparency and responsibility – can ensure that science serves to protect people and not to legitimise new forms of dependence.

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