Tag: Nicotine

Study Warns Flavored Nicotine May Be More Addictive

Certain nicotine flavors could be more addictive than others, according to researchers from the Yale School of Medicine, who found that rats preferred the combination of flavorings and nicotine to just the flavorings or unflavored nicotine on their own. The study suggests that sweeteners play a greater role in nicotine preference for females, while flavors are more influential for males.

Published in the journal Nicotine & Tobacco Research, the effects of the sweeteners sucrose and saccharin, as well as the commonly used flavor additive cinnamaldehyde (the principal chemical of cinnamon) in nicotine were tested on rats. Female rats showed the highest nicotine preference when combined with sucrose, while males preferred nicotine combined with cinnamon. They also found menthol flavoring increases oral nicotine intake in male rats but not in females.

The study says that although flavors do not significantly impact nicotine absorption, they significantly influence user satisfaction and increase the likelihood that people will continue using nicotine products.

March 18, 2025
France Extends Ban to Nicotine Pouches

Two weeks after banning disposable e-cigarettes, France notified the European Commission it would ban the sale of nicotine pouches as well, joining countries that include Austria, Belgium, Germany, and Luxembourg.

“The French decree follows in the footsteps of the decision on 13 February to ban disposable e-cigarettes,” a tobacco industry source told Euractiv. “French regulators have been monitoring developments in the new tobacco products sector. Health authorities became alarmed, and the government decided to activate the legislative levers available to it.”

With an expected annual growth rate of 6.2%, the European nicotine pouch market could reach €1.06 billion by 2030. Europe’s 2014 Tobacco Products Directive covered all traditional tobacco-containing products and included provisions for new tobacco products, however, nicotine pouches contain no tobacco, and thus remain unregulated at the EU level.

Tobacco and nicotine products are not on the EU’s agenda for 2025, however, the Polish Presidency Council (which sits atop the Commission along with Denmark and Cyprus until June) is looking to move forward with discussions for taxing alternative tobacco products and possibly revising the Tobacco Products Directive.

February 26, 2025
Fast-Dissolving Nicotine Strip Makes First Cut for Grant

CTT Pharmaceutical Holdings said it has advanced past the initial round in its application for a National Science Foundation (NSF) grant for its patented fast-dissolving nicotine strips. The company is now among a few thousand remaining applicants from an initial pool of over 12,000 applicants. Acceptance into the program would give CTT government backing and allow for extensive research and testing to help in the development of its technology.

“To make it past the first round of applicants is a huge accomplishment by itself and shows that the NSF sees potential value for our technology within the tobacco industry,” said Ryan Khouri, CEO of CTT Pharma. “Currently there are no fast-dissolving, low-dose nicotine strips on the market, as most oral products stay in the mouth for an excessive amount of time.”

The company’s technology aims to address a significant public health issue, as classified by WHO. CTT said it expects to receive a response by late April.

February 12, 2025
Tobacco Control’s Nervous Breakdown
Photo: Xalanx

Innovation in the recreational nicotine market is revolutionizing the tobacco industry and disrupting tobacco control.

By Clive Bates

In his groundbreaking 1997 book, The Innovator’s Dilemma, Clayton Christensen defined the concept of “disruptive innovation.” The term is often used carelessly, but disruptive innovation has several characteristics that apply in today’s tobacco and nicotine market. In essence, it is a theory of how entrants to a market can challenge incumbents by focusing on unmet needs using novel business models exploiting simple enabling technologies.
In the nicotine market, the lithium-ion battery provided a critical enabling technology with sufficient power and energy density to replace combustion with electrical heating to create an inhalable aerosol in a compact and convenient form. Once the concept took off in the early 2010s, the technology rapidly evolved through at least four major generations during the decade. The disruption has never stopped, and the emerging incumbents in the vape industry now face disruption from disposable single-use vape products. It isn’t just technology; the business model has changed and adapted over time, embracing user-driven innovation, new retailing models such as specialized vape shops and international e-commerce, and a pro-health marketing proposition spread through social media.
A new wave of innovation is now breaking with the rapid rise of oral nicotine pouches. This newer trend may prove even more disruptive—a low-tech, low-cost nicotine delivery with negligible health consequences, no intrusion on others and none of the stigma attached to tobacco. Through vaping, consumers have deconflated tobacco and nicotine use and are now primed to adopt this technology.
The regulatory environment also played a critical role, but more for what it didn’t do than what it did. In the United States in 2009, the U.K. in 2010 and the European Union in 2013, there were failed attempts to classify and regulate vaping products as medicines. Several core pharmaceutical regulation concepts are hostile to vaping. Vaping products are not smoking cessation therapies but pleasurable consumer alternatives to smoking that require nicotine delivery equivalent to cigarettes. Medicine regulators are not at ease with pleasure, or what they would call “abuse liability,” yet pleasure is integral to their success as consumer products.
Let’s delve deeper and ask who is disrupted and how.
First, the incumbent tobacco companies. In the standard model of disruptive innovation, these giants would be caught off guard by fast-moving entrants bringing new technology to a vanguard of early adopting consumers, rapidly changing the market dynamics. This would be felt most keenly as a loss of “pricing power” (the ability to raise prices to compensate for declining cigarette volumes) and a squeeze on margins and revenue in the profitable incumbent cigarette business. This should happen as the existing customer base of people who smoke is exposed to a wide range of low-cost alternatives without many downsides. So far, I don’t think this squeeze on the cigarette business has happened to anything to the extent it might have and still could, even though the companies have entered these markets and developed heated-tobacco products. The reason is that regulators are slamming on the brakes in response to activist and political pressure—disrupting the disruption. Regulatory excess has combined with activists and academics working tirelessly to nurture false risk perceptions and reinforce doubt about the wisdom of stopping smoking by switching to a reduced-risk product. The tobacco industry has been protected from the most severe disruption with the unintentional help of the tobacco control mainstream.
Second, disruption has wrong-footed regulators and legislators. In response to rapid changes in the market, regulators and legislators have blundered in without first understanding (or perhaps without caring about) the complex adaptive system in which their rules would be applied. Because the new products function as economic substitutes for cigarettes, we expect three primary responses to excessive regulation: more smoking than there otherwise would be, more illicit trade in the new products, and consumers adopting risky workarounds, such as mixing their own flavored e-liquids. For example, limiting nicotine strength in the European Union made it harder to bring to market the pod devices that have been successful in reducing smoking in the United States. Flavor bans in the United States made vapes less appealing and caused more people to smoke, in some cases including young people. The prescription-only availability of vapes in Australia has led to a chaotic, lawless mess, with more than 90 percent supplied via informal, illegal channels. With their mission to protect the young from vaping, regulators forgot that in a world without vaping, many young people would smoke and, therefore, are benefiting from vaping.
Third, the rise of the confident consumer. Consumers are the primary beneficiaries of the radical reduction in health and welfare detriments of smoke-free products. We are used to smokers burdened with regret, challenged with stigma and punished by anti-smoking policies. But all of that is driven by the health implications of smoking and the policy response that started in the early 1960s. How does the recreational nicotine consumer change if they are no longer troubled by the health and welfare implications of nicotine use and related policies? Simple economic theory suggests that if the costs and nonmonetary detriments of nicotine use fall, then demand will rise. It is likely, in my view, that there will be new users of nicotine who would never have become smokers in the absence of much safer products. For some, that is profoundly disturbing. For me, it is almost an inevitable consequence of having far lower risks and there being a latent demand for the real or perceived hedonistic, functional and therapeutic benefits of nicotine. Public morality may be shocked, but more people (of any age) using much safer products should not cause a public health crisis—we would be moving to substance use more like drinking coffee.
Fourth, the existential threat to the tobacco control complex. The public discussion of the emerging landscape of low-risk consumer products seldom focuses on the interest group that is most vulnerable to disruption: the mainstream of tobacco control. It is a complex of interests comprising nonprofit activists, academics, medical and health societies, major institutions (such as the World Health Organization or the U.S. Food and Drug Administration), philanthropists and research-funding bodies. The problem for the mainstream of tobacco control is that without serious harm, the whole movement loses its purpose and its reason to exist. When it comes to low-risk alternatives to smoking, this complex is profoundly confronted by the threat of having nothing to control, no case for intervention and no reason to be. It is a powerful incumbent interest group challenged by new technology, new suppliers and new consumer confidence.
As a result, the mainstream of this interest group has rejected tobacco harm reduction as a strategy for addressing its own notional goals of reducing death and disease from tobacco use. Instead, it has mounted a rear-guard defense based on a range of strategies, including the following:
Falsely implying that noncombustible products are no less risky than cigarettes, that data is too uncertain or short-term, or asserting that reduced risk is no more than a marketing claim of tobacco companies.
Asserting that harm reduction is merely a commercial strategy of tobacco companies. The aim here is to attach the reputational baggage of “Big Tobacco” to these new developments. Yet, many independent experts support tobacco harm reduction, and it is good if tobacco companies adopt a business model aligned with reducing health impacts.
Excluding or stigmatizing contrarian opinions and creating sealed bubbles open to groupthink. The WHO Framework Convention on Tobacco Control has taken this to new extremes.
Shifting emphasis to problematize nicotine rather than the “tar” of cigarette smoke that is the cause of nearly all tobacco-related disease. We are hearing more about “addiction” and less about cancer. Yet, a dependence only meets the definition of addiction if there is serious net harm to the user.
A relentless focus on the supposed interests of children without recognizing that would-be smokers among adolescents also benefit from low-risk products and that the demand for nicotine has persisted across generations for hundreds of years. Young people have an interest in the health of the significant adults in their lives as carers, breadwinners and role models.
Pressing for prohibitions or equivalent regulation to cigarettes, often with manipulation of language to imply equivalent risk, for example, by stating that heated-tobacco products produce “smoke” or that all tobacco products should be treated the same even though they have very different risks.
A blunt refusal to face trade-offs (for example, between the interests of youth and adults) or unintended consequences (for example, increases in smoking) arising from favored policy positions.
I have watched on in horror as the leadership in tobacco control, albeit with many honorable exceptions, has dogmatically denied and suppressed the opportunity to radically reshape the recreational nicotine market to cause vastly reduced harm and avoid hundreds of millions of premature deaths. It looks like a nervous breakdown is developing in tobacco control in response to profound disruptive innovation. I doubt they will survive it.

Clive Bates is the director of Counterfactual Consulting and the former director of Action on Smoking and Health (U.K.).
March 1, 2024
Dispelling Myths
Photo: Elena Milevska

A disturbingly larges share of doctors believe that nicotine causes smoking-related diseases.

By George Gay

For a long time, people involved in tobacco harm reduction (THR) have bemoaned the fact that many doctors wrongly believe that consuming nicotine causes smoking-related diseases. Clearly, the concern as far as THR advocates are concerned is that, logically, these doctors are unlikely to recommend that smokers transition from combustible cigarettes to other forms of nicotine delivery, such as those afforded by electronic cigarettes, nicotine pouches and, one must assume, even nicotine patches.
This concern was highlighted in a July 20 press note issued on behalf of the Foundation for a Smoke-Free World (FSFW), which said that a survey of more than 15,000 physicians in 11 countries had found, in part, that 77 percent of doctors mistakenly believed nicotine caused lung cancer, and 78 percent mistakenly believed it caused atherosclerosis. The Doctors’ Survey was carried out online by Sermo with doctors based in China, Germany, Greece, India, Indonesia, Israel, Italy, Japan, South Africa, the U.K. and the U.S.
“It is imperative that doctors get the proper training to learn the facts about nicotine and tobacco harm reduction options that can help their smoking patients quit,” Muhammad Ahmed, the FSFW’s director of health and science research, was quoted in the press note as saying. “With more than 7 million smokers dying annually from smoking-related diseases worldwide, many lives can be saved if doctors become more knowledgeable about the cessation tools available.”
Now, the FSFW is inviting researchers to submit (contact support@smokefreeworld.org) proposals to further analyze the Doctors’ Survey findings and propose programs to help improve doctors’ “fluency about smoking cessation and tobacco harm reduction.”
The report of the Doctors’ Survey has much to recommend it, and I would urge anybody interested in THR to read it. One of its strengths, I would suggest, is that it is a practical attempt to help address the chronic problems associated with doctors being generally ill-informed about nicotine. And it is to be hoped that this practical emphasis continues as researchers further analyze the survey’s findings and propose remedial actions. It would be unfortunate if there were a focus on analysis that led to academic drift. We should not lose sight of the fact that this is about helping smokers, not about helping indigent academics—the words “more research is needed” should be proscribed.

Primary Sources

While generally supporting this initiative, I have a few concerns and questions about some of the issues that the survey raises. There is what looks like an unnecessary reference to IQOS in one of the report’s tables, something of an “own goal” I would have thought, given that the FSFW comes under attack for the source of its funding, notwithstanding such attacks might be unwarranted and unfair.
And I hope that whatever comes out of the proposals for improving doctors’ “fluency about smoking cessation and tobacco harm reduction,” it clears up a couple of questions. Doctors in Japan are said in the survey report to believe mistakenly that “light” cigarettes are less harmful than other cigarettes, but what are doctors working in the EU to make of this “mistake” when the authorities there impose a limit on deliveries? Is it out of malice or a sense of a lightness of being that the authorities in the EU allow only the sale of “lighter” cigarettes? And a related question would ask if anybody knows whether there is any point in doctors recommending smokers cut their consumption. Does anybody know if the risks of smoking are proportionate to consumption levels—in respect of delivery levels per stick and/or by daily stick consumption?
More importantly, the question arises as to whether we know if doctors are the primary source of the information on smoking and quitting that people absorb and act upon. If so, the direction of the FSFW’s travel seems correct and important. If not, it would seem irrational to spend a lot of time and money trying to improve the training of doctors in this area, especially given that if they haven’t figured out the role of nicotine by now, it is possibly going to take a lot of effort to get through to them. I certainly cannot see how the doctor route could be universally applicable given that many governments oppose at least some aspects of THR, and many health services are at least partly state institutions.
A cursory internet search indicated that, in the U.K., patients had on average 8.7 consultations with general practitioners during 2018–2019, 3.3 of them face-to-face. Compare that with the uncountable number of times these same people would have gawped at their mobile phones. So, in a country such as the U.K., where the government is convinced of the effectiveness of THR, it would perhaps be better for it to use social media to get messages across. I am not advocating the usual sort of official messages that comprise little more than a tissue of lies but messages simply about the relative safety of nicotine as the government sees it. Otherwise, messages could be included, for instance, on the shirts of professional sorts of people, on public transport and on public buildings. And given the increasingly authoritarian nature of the U.K. government, perhaps it might consider the compulsory tattooing of people with these important messages.
Another problem was brought to light when Ahmed said that it was imperative for doctors to receive the proper training to learn the facts about nicotine and tobacco harm reduction options that can help their smoking patients quit. The obvious questions arise as to who gets to decide what amounts to proper training and what the facts are in a postmodern world. The facts, for example, as they apply to the use of THR principles and as they are decreed by the authorities in India and the U.K., are likely to be very different.
The World Health Organization, though paying lip service to THR, opposes the shift from inhaling tar and nicotine to inhaling just nicotine. And the U.S. Food and Drug Administration, whose influence stretches beyond the U.S., while also paying lip service to THR, has done much to discourage smokers making such a shift. In fact, the FDA, at the same time, has de facto promoted the smoking of tar-delivering, low-nicotine combustible cigarettes. What is a trainee doctor to make of such policies—such implied facts?
Of course, such issues will not have escaped the attention of those behind this initiative, but it concerns me that any attempt at trying to resolve them, either universally or on a state-by-state basis, will simply lead to delays in reaching THR objectives. The vaping advisory industry, in all its guises, should not be seen as being more important than the vaping industry.

Evaluating the Curriculum

But I have a bigger concern. The ad nauseam message coming from governments and organizations such as the WHO and the FDA is that “[c]igarette smoking remains the leading cause of preventable disease, disability and death ….” In fact, that quote comes from the Centers for Disease Control and Prevention and refers to the U.S.
At the same time, the message coming from the Doctors’ Survey is that most doctors are ill-informed about issues surrounding smoking and nicotine consumption because they have received little or no training on smoking cessation. “This may reflect the cursory training they’ve received in smoking and harm,” is a quote from the survey referring to doctors in Italy.
Let me paraphrase these two positions:
Cigarette smoking is the leading cause of preventable disease, disability and death.
Most doctors receive only cursory training in respect of the leading cause of preventable disease, disability and death.
It seems I am being asked to believe that doctors, charged, in part, with helping people avoid sickness, are not being properly trained in respect of the most threatening health concern of all. How can I reconcile these two positions or overcome the apparent state of insanity they describe? I could assume, I suppose, that those who devise the curriculums at the base of doctor training courses are not in full control of their mental faculties, that they insist doctors should, when you visit them, be able to rattle off the names of the 206 bones in your body but not be able to give you sound advice on the leading cause of preventable disease, disability and death. On the whole, I find such an explanation unlikely given that we are talking about the curriculum advisers in 11 countries. They cannot all have taken leave of their senses.
So, I am left with the conclusion that either No. 1 or No. 2 above must be wrong, and I am leaning toward the idea that it is No. 1 that is wrong. But before I expand on this idea, I need to make three points. Firstly, I am not saying cigarette smoking is anything but hugely harmful. I think it stands to reason that inhaling anything but pure air is not a good idea and is likely to cause you harm. Secondly, I am not saying cigarette smoking was never the leading cause of preventable disease, disability and death. Thirdly, I have read in recent times about three things reported to be the leading cause of early deaths in humans: tobacco smoking, outdoor pollution and poor diet.
Above, I quote Ahmed as saying more than 7 million smokers die annually from smoking-related diseases worldwide. But what does this mean? It is arguably a completely open-ended figure, one that might or might not approach or even surpass the WHO’s 8 million. OK, you could argue the “more than 7 million” is just a throwaway, ballpark figure aimed at underlining the severity of this issue, but surely it is necessary to have more than a ballpark figure before we start trying to build a sturdy quit-smoking edifice?
Recently, The Guardian newspaper’s health editor, Andrew Gregory, made the point that long-term exposure to air pollution is associated with chronic conditions such as heart disease, asthma and lung cancer.
Clearly, separating many cigarette-smoking deaths from pollution-related deaths must be difficult, if not impossible, so I find it odd that health professionals are willing to accept and work on the basis of what seem to be highly dubious smoking-related-disease figures. Why are health professionals so keen on expending huge amounts of effort and money addressing what they blindly accept to be the problems caused by smoking, which, by the way, are likely decreasing and which individuals can address for themselves, rather than expend that effort and money addressing the much bigger and growing health problem posed by pollution, over which individuals have next to no control and which are going to get worse as the population of the world approaches 10 billion and becomes even more concentrated in megacities? It is time to ask “cui bono” and “cui malo”?
George Gay is Tobacco Reporter’s European editor, but his territory spans the globe. Based in London, George has covered the tobacco industry since 1982, initially for a U.K.-based publication and since 2004 for Tobacco Reporter. George’s understanding of industry issues, combined with his keen sense of observation and dry wit, have earned him a loyal following among Tobacco Reporter’s readers.
October 1, 2023
Gunther: Truth Initiative Wants End of Nicotine

Image: luciano

The Truth Initiative’s endgame plan amounts to nicotine prohibition, according to Mark Gunther.
Writing in Filter, Gunther cites a recently released Truth Initiative report in which the organization outlines its “strategy to move toward the end of commercial tobacco and nicotine use.”
“A tobacco-free future is possible,” said Robin Koval, the president and CEO of the Truth Initiative, during an online panel discussion about the plan.
Critics fear that the organization’s focus on nicotine prevention could keep combustible cigarettes around longer, however.
“The endgame should be reducing premature deaths from tobacco, not the eradication of nicotine, which is not going to happen and is misguided policy,” said K. Michael Cummings, a veteran tobacco control expert and professor at the Medical University of South Carolina.
“Changing the objective from reducing smoking-related deaths and disease to destroying the tobacco industry and eliminating nicotine use is completely misguided,” said Alex Wodak, a physician and the director of the Australian Tobacco Harm Reduction Association.
In the near term, according to Gunther, the Truth Initiative wants a national ban on menthol cigarettes and cigars; a ban on flavored vaping products; sales of nicotine products restricted to adult-only stores; a reduction in the number of places selling tobacco; reduced nicotine levels in cigarettes; and improved access to smoking cessation drugs. Medium-term and long-term, the group wants to develop new quitting options; cap nicotine levels in all products; and prohibit the sale of tobacco and nicotine products completely.
In the panel discussion, Koval said that it is misleading to describe the group’s endgame strategies as prohibitionist and that the targets are manufacturers and retailers. Critics disagree with this as well, arguing that the Truth Initiative is one of the first to call on the U.S. Food and Drug Administration and the Department of Justice to enforce rules.
“No group has pushed harder or yelled louder for FDA and DOJ [Department of Justice] to outlaw vaping and kick in the doors of anyone perceived as disobedient,” said Alli Boughner, vice president of American Vapor Manufacturers. Boughner said the endgame plan is “totally dislocated from the real world or even basic human decency.”
Harm reduction advocates take issue especially with the Truth Initiative’s lack of distinction between harms resulting from tobacco versus harms resulting from nicotine.
“Nicotine should join the list of socially acceptable psychoactive substances like caffeine, like the moderate consumption of alcohol and, increasingly, like cannabinoids,” said Clive Bates, a harm reduction advocate. “We don’t lose our minds when young people have a drink or take coffee.”

July 21, 2023
The Pharmacology of Nicotine

Photo: Richard Villalon

The fascinating workings of a widely misunderstood chemical

By Grant Churchill

In this article, I will describe the pharmacology of nicotine. I will guide you along nicotine’s journey, starting with how it gets into a person, explain what it does once inside by interacting with specific receptors and finally, how it is inactivated and leaves.
Due to its chemical properties, nicotine can exist in two forms, depending on acidity, which controls its ability to be absorbed and, in turn, the effectiveness of delivery by different routes of administration. For example, certain forms of smoked tobacco must be inhaled to absorb nicotine, such as cigarettes, whereas others, such as cigar and pipe tobacco, are not inhaled but nicotine is still absorbed.
It might be useful for the reader to know where I’m coming from in writing this article. I’ve got a professional interest in how drugs work as I do research and teach in this area and find the pharmacology of nicotine fascinating and convey this to medical students. I’ve also got a personal interest as both my parents smoked and died from cancer. So, I wonder if vapes were available 40 years ago, would my parents still be alive? And now, should I be concerned that my adult son is vaping?

Routes and Rates

I’ll now describe in more detail how nicotine gets into the body and then the brain. This depends on the fascinating interplay between the route of administration and the chemical formulation, for example, free base or salt of nicotine. Regarding the route of administration, one can have an intuitive and qualitative understanding by considering the number of barriers and distance from the site of application to the brain.
When inhaled, nicotine has a short journey with few barriers as it is absorbed into the oxygenated arterial blood and goes from the heart to the brain within 10 seconds.
When swallowed, nicotine has a much longer journey with several barriers as it has to make its way through the stomach on to the small intestine before it can be absorbed into the bloodstream. Then it is in the deoxygenated venous blood that goes to the liver, then through veins to the heart, then through the lungs, where it finally meets the starting point for the inhaled nicotine. Importantly, the liver acts as a paper shredder for drugs and metabolizes them before they are delivered to the rest of the body.
When applied by a patch, the skin provides an additional barrier before nicotine can enter the bloodstream. Surprisingly, an intravenous injection of nicotine results in a slower route to the brain than inhalation.
For the intuitive understanding of the routes and rates, one can think about the physiological role of each system. The job of the lungs is to absorb large amounts of oxygen and quickly deliver it to the brain, the importance of which is driven home by considering that consciousness is lost within tens of seconds if inhibited. In contrast, the job of the gastrointestinal tract is to absorb food for energy, which is not needed at the pace of oxygen. Moreover, the job of the liver has evolved to protect us from the remarkably diverse and potentially harmful chemicals we consume in our diets, and in this regard, a drug is just another nonfood or non-nutrient to be inactivated and removed.
The uptake of nicotine can be more precisely studied quantitatively by monitoring nicotine in the blood and graphing this over time. This reveals an initial increase, a peak and then a tapering off, and numbers can be put to the time and concentration at the peak and the area under the curve. The hit comes from a combination of the speed of the peak and the maximum concentration, and the craving comes from when the concentration falls below a critical activity threshold. The different routes of administration show characteristic concentration over time profiles, with inhaled nicotine showing a fast peak within minutes whereas a patch-delivered nicotine shows a slow increase, taking an hour to peak. This has implications in the user experience and the success of nicotine-replacement therapies for tobacco harm reduction. The rate of decrease in nicotine concentration is similar for all routes of administration due to the same elimination mechanisms: a combination of metabolism by the liver and excretion by the kidney into the urine.

Crossing Barriers

The chemical formulation of nicotine as a salt or free base has a major impact on its uptake into the body as only the latter gets in. The chemical basis of this can be understood by considering a vinaigrette, which forms two layers, with the oil floating on a layer of vinegar and table salt (sodium chloride) dissolving only in the vinegar. This demonstrates that molecules can be watery or oily and only mix with their own kind, as summed up by the adage that oil and water don’t mix. Bringing this back to biology, the barriers to uptake of nicotine are cells that form layers like brick walls to separate the contents of our gastrointestinal tract from blood and blood from the organs. The cell’s barrier is its surface membrane called a bilayer, which is an inside out soap bubble with a watery surface and an oily interior forming the barrier. A water-loving nicotine salt cannot cross the oily interior whereas the oily free base of nicotine easily crosses.
The ability of nicotine free base to easily cross cell membranes is the mechanistic explanation of why nicotine can be absorbed from pipe and cigar smoke held in the mouth whereas cigarette smoke must be inhaled. The processing of the tobacco alters the chemical composition and acidity, resulting in cigarette flue-cured tobacco being acidic with nicotine salt whereas air-cured pipe tobacco is alkaline with nicotine free base. For a fuller explanation, we must again consider how chemistry interacts with biology. Smoke from acidic tobacco (nicotine salt) is less harsh and irritating and can be inhaled deeply into the lungs, where the large surface area (approximately the size of a tennis court) compensates for the inability of the salt to cross membranes.
Nicotine is always present in both forms, and the acidity controls the relative amounts of salt to free base with only a tenth of a percent in cigarette smoke being the free base compared to 50 percent in pipe smoke.
The trade-offs between the amount of nicotine that is bioavailable and how deeply it can be inhaled to take advantage of the large surface area of the lungs can also explain the nicotine salt craze in vapes. Nicotine salt formed by adding benzoic acid leads to a “smooth” taste, enabling deep inhalation of higher concentrations of nicotine.

How it Works Inside

Now that nicotine is in the body, I’ll describe its effects and how it is active. Nicotine affects cognition, body function and mood. The effects of nicotine on cognition relate to attention and memory and it has been suggested to be a “work” drug as opposed to what most of society would think of as a recreational or “fun” drug. The effects of nicotine on body function mostly relate to heart rate and blood pressure. The effects of nicotine on mood are relaxation and euphoria, arguably two of its major effects as nicotine stimulates a reward pathway in our brains the causes one brain region to stimulate other regions involved in emotion by releasing the neurotransmitter dopamine. Neurotransmitters are chemical messengers that enable communication between the brain cells termed neurons. Very generally, dopamine signals reward or the anticipation of reward—think sex, drugs and rock ’n’ roll, and these days, smartphones—which leads to pleasure and risk of dependence. Nicotine itself acts by mimicking the neurotransmitter acetylcholine, which is involved in learning, memory and attention, which fits with its subjective effects mentioned above.
Remarkably, all the diverse actions of nicotine arise from it acting on the same pharmacological target: the nicotinic acetylcholine receptor. This receptor spans the surface membrane of a cell and acts as a gated pore that allows ions such as sodium to flow through and trigger a wave of voltage change that sweeps from one end of the cell to the other. The binding of acetylcholine, or nicotine, results in opening and turning on the signal—but with prolonged presence, the gate on the pore jams shut in what is termed “desensitization.”
So, nicotine has time-dependent effects: Over a period of minutes, the nicotinic acetylcholine receptors open and release dopamine, but after several hours in the presence of nicotine, many of the receptors desensitize, dopamine levels fall, and more nicotine is required to return to the higher level of dopamine. Over a period of weeks, the neuron responds by increasing the number of nicotinic acetylcholine receptors, but most are desensitized, and if nicotine is no longer present, dopamine levels fall, giving rise to physiological withdrawal and addiction. Addiction at the molecular level is related to the structure of the nicotinic acetylcholine receptor, which is made up of five cylindrical subunits arranged side by side in a circle to form the pore. Each subunit is given a Greek letter designation, and in a mouse model, addiction relates to the presence or absence of the beta subunit.

Chemical Inactivation

The pharmacological effects of nicotine wear off with time, not from the above desensitization mechanisms but through chemical inactivation and excretion. Nicotine in the blood has a half-life, the time for a given concentration to be reduced by half, of about two hours. Nicotine declines over time through processes common to all drugs in which the underlying principle is to convert a drug from an oily compound to one that is watery. Water is watery due to it being composed of hydrogen and oxygen, therefore introducing oxygen into nicotine makes it watery.
This chemical transformation occurs in the liver by the enzyme (a molecular machine) cytochrome P450, which forms the major metabolite cotinine. As cotinine has a half-life of about a day, it can be used to examine past nicotine exposure, often by health insurance companies. Cytochrome P450 is a family of enzymes, and different forms are more or less active in converting nicotine to cotinine; the specific form varies between individuals, and certain forms are more frequent in a given ethnic group. For example, a less active form of the enzyme is more prevalent in individuals with Black or Asian heritage. Cotinine or its metabolites are finally removed from the body through the action of the kidneys and excreted into the urine. Again, the effect of acidity on nicotine can be employed by acidifying the urine to increase the fraction of salt, which cannot be reabsorbed back by the body, which thereby increases nicotine excretion.

Addressing Misunderstandings

Lastly, there are many controversies surrounding nicotine based on misunderstanding, half-truths and myths. The major health consequences of smoking are due to chemicals other than nicotine produced during combustion of tobacco, so other methods of nicotine delivery provide for tobacco harm reduction. For example, the relative health harms are such that vaping is a method for smoking cessation endorsed by the National Health Service in the U.K. and promoted as such by the government based on the best current scientific evidence.
Nicotine was used as a pesticide and can be toxic, but as Paracelsus famously stated, the dose makes the poison; any chemical can be toxic, including seemingly innocuous water, or an exceptionally toxic substance such as Botox can be used safely at a lowered concentration. Nicotine may have bona fide therapeutic use beyond smoking cessation in Alzheimer’s disease, Parkinson’s disease, schizophrenia and obesity. Intriguing evidence has been published regarding all these disorders, but the studies were small, leading to equivocal results.
Larger studies are needed, but the demonization of the tobacco industry for past wrongs is tainting and hampering the ability of scientists and physicians to obtain funding and conduct large, definitive trials. Given that psychedelic drugs, which were made illegal and vilified in the 1960s, are experiencing a renaissance to treat depression and post-traumatic stress disorder, there is hope that nicotine can be separated from smoked tobacco and used or not based on the evidence.

Grant Churchill is a professor of chemical pharmacology at the University of Oxford.

May 1, 2023