After a few vigorous puffs of a burning cigarette, a smoker’s lungs will be filled with a toxic cloud of more than 5,000 different substances. Their combined effects on health are well known: cancer, heart disease, stroke, chronic obstructive pulmonary disease and many more conditions. However, the most famous ingredient of a cigarette — nicotine — has generally not been considered a culprit in these health effects.
Nicotine is an alkaloid compound made by plants to deter herbivores, and it has been used as an insecticide. It poisons insects by binding to acetylcholine receptors in their nervous systems and causing their nerves to fire uncontrollably. In people, nicotine activates similar receptors throughout the nervous system, including those in the brain that affect the release of the feel-good molecule dopamine. The positive feelings this produces are why nicotine is addictive, and one reason why smokers crave cigarettes.
Although the addictive qualities of nicotine are well known, the damaging health effects of smoking are usually attributed to more-obvious toxins such as polycyclic aromatic hydrocarbons (PAHs), cadmium and the sticky brown tar left inside the lungs. “It has been said since the 1950s that people smoke for the nicotine and die from the tar,” says Aruni Bhatnagar, director of the American Heart Association’s Tobacco Regulation and Addiction Center at the University of Louisville, Kentucky.
But some researchers think that nicotine’s influence on health could extend beyond just its addictive nature. Receptors that respond to nicotine are found not just in the brain, but also in tissues such as muscle. “It changes lots of functions in our bodies,” says Maciej Goniewicz, a nicotine pharmacologist at Roswell Park Comprehensive Cancer Center in Buffalo, New York. “It’s not a harmless compound.”
Evidence for direct deleterious effects of nicotine consumption is limited. “It is hard to sort out because most nicotine exposure data comes from cigarette smoking,” says Neal Benowitz, a physician and nicotine researcher at the University of California, San Francisco. With so many toxic compounds in tobacco smoke, separating nicotine from the rest of the noxious milieu has been a struggle. “We’ve done a poor job of dissecting out the various components of cigarette smoke,” says Gerry McElvaney, a pulmonary physician at the Royal College of Surgeons in Ireland, Dublin.
Interest in the effects of nicotine is blossoming, partly because of the proliferation of e-cigarettes, or vapes. Vaping could provide a nicotine hit without the cancerous baggage, but it has become fiercely controversial owing to concerns that people who have never smoked — especially adolescents — will become hooked. In this new context, delineating the effects of a purer stream of nicotine is important, and numerous associations are being made, including purported impacts on heart health, cancer and brain development.
Issues of the heart
When a smoker tugs on a cigarette, their heart pumps harder, their blood pressure increases and certain blood vessels dilate or constrict. These effects are partly due to nicotine, which triggers the release of various neurotransmitters and hormones such as epinephrine. This process happens whether nicotine is inhaled from a cigarette or an e-cigarette, or chewed in the case of smokeless tobacco. What these acute impacts mean for long-term cardiovascular health, however, is disputed.
Researchers at the American Heart Association think that the stress nicotine puts on the heart is concerning. “We believe that much of the cardiovascular effects of smoking are because of nicotine,” says Bhatnagar. When nicotine is inhaled, it changes the electrical conductivity of the heart that keeps it beating in sync. Nicotine can knock this delicate timing off and promote abnormal heart rhythms, says Bhatnagar. Nicotine has also been implicated in stoking inflammation in heart and lung tissue, says Laura Crotty Alexander, a pulmonary biologist at the University of California, San Diego in La Jolla.
Some researchers think that nicotine has only a small effect on heart health. “Nicotine is a minor player with respect to smoking-induced cardiovascular disease,” says Benowitz. He points to studies of snus — a chewable tobacco product that is popular mainly among men in Sweden and is gaining traction elsewhere — which do not generally show a detectable rise in heart problems among people who use it. However, some studies have suggested that a heart attack or stroke is more likely to be fatal for someone who uses snus, and another found that stopping snus use after a heart attack reduced subsequent short-term mortality. This suggests that nicotine could be more harmful to someone with underlying cardiovascular disease, Benowitz acknowledges. And in January, a study suggested that smokeless tobacco increases the risk of peripheral artery disease to a similar extent as does cigarette use.
The method of nicotine delivery might also affect its impact. Smoking and vaping both deliver a concentrated hit; nicotine patches, which are used by some people to help them quit cigarettes, provide a more gradual dose.
This could be an important difference. The nicotine hit from smoking and vaping might produce more noticeable spikes in blood pressure. Repeated over time, this could increase the stiffness of arteries and increase pressure on the heart. “Nicotine patches and gum are not the same as taking a drag on a cigarette,” says Bhatnagar. “You need that hit, and that’s the hit that causes the cardiovascular issues.”
Cigarette smoke is rich in tumour-promoting substances, including arsenic, aromatic amines, benzene, ethylene oxide, formaldehyde and PAHs. Evidence for nicotine to join that list of direct human carcinogens is limited.
In vivo animal studies of nicotine exposure have returned mixed findings on the compound’s link with cancer. There is evidence that nicotine inhibits apoptosis — the process by which cells self-destruct, which is an important guard against tumour formation — in cancer cells by binding to cholinergic receptors. Nicotine also ramps up the formation of new blood vessels, which can supply nutrients to a hungry tumour.
Nicotine’s ability to drive inflammation might also be of note. Most immune cells have receptors that nicotine can hack to sabotage T cells, inhibit antibody formation and interfere with immune messaging. “Someone chronically exposed to nicotine might have chronic inflammation,” says Goniewicz. “There is speculation that it might contribute to increased risk of cancer.” A 2021 study that examined the impact of nicotine on mouse models of metastatic breast cancer concluded that chronic exposure to nicotine encouraged the spread of tumours by ramping up the amount of neutrophils, a type of white blood cell. “High levels of neutrophils are damaging,” says Robert Tarran, a physiologist at the University of North Carolina at Chapel Hill.
The evidence is not unanimous, however, and there is little known about how this relates to people. “Some animal models have found that nicotine does promote cancer,” says Benowitz, “but the evidence, for me, is not convincing in tying it to cancer in humans.” A 2009 study of long-term nicotine replacement therapy — specifically, a nicotine gum — found no effect on cancer risk, although nicotine exposure from gum is lower than would be expected from vaping or snus. Any connection between nicotine and human cancers remains unclear. “From animal and cell studies, yes, nicotine is doing something,” says Goniewicz. “How this translates into a risk for the user, we don’t know.”
A developing problem
The strongest evidence against nicotine relates to its impact on brain development. Activation of acetylcholine receptors helps to regulate brain development and growth. Nicotine binds to these receptors and can therefore interfere with this process. It has been shown that nicotine is responsible for up to almost 50% of the overall impact that tobacco smoke has on brain circuitry development in male rats.
Nicotine subtly changes neurons in addicted adults, but its impact is greatest in the developing brain, where circuitry is less mature. Exposure in the womb is an independent risk factor for developmental disorders, such as attention deficit hyperactivity disorder, says Kjersti Aagaard, a maternal-fetal physician at Baylor College of Medicine in Houston, Texas. The brain of a developing fetus or neonate could be especially vulnerable. “No amount of nicotine is known to be safe in pregnancy. None,” Aagaard says. “If you are exposed to nicotine in the womb, there could be lifelong consequences.”
Nicotine exposure in the womb is associated with a higher risk of addictive behaviours in adulthood. Babies could also be exposed to nicotine while breastfeeding. A study last year reported that when female mice were exposed to nicotine, they passed the compound to their pups in their breast milk, and these pups experienced long-lasting behavioural changes.
Beyond just neurological impacts, some epidemiological studies — but not all — have linked the use of e-cigarettes during pregnancy with higher rates of preterm and low-birthweight deliveries compared with pregnancies in which the mother abstained from all tobacco products, Aagaard says. This in turn brings more risks for children, she adds, such as a greater risk of developing metabolic disorders.
The UK National Health Service describes e-cigarettes as safer than smoking for pregnant women, but it notes that there is little research to support the safety of e-cigarettes beyond that. It recommends pregnant women use nicotine patches and gums to stop smoking.
Nicotinic acetylcholine receptors are involved in forming brain circuits during childhood and adolescence. The brain’s prefrontal cortex, responsible for marshalling judgement, impulsivity and risk-taking, does not fully mature in people until their early twenties. There is a strong suspicion that nicotine can throw a spanner in the works throughout this time — a particular concern given the growing popularity of vaping among young people. But the effects of e-cigarettes on teenage brain development is yet to be made clear. “Nicotine is definitely harmful to the developing adolescent brain in animals,” Benowitz says. “In humans, it is harder to establish.”
Before the advent of e-cigarettes, there was less interest in finding an answer to this question — there are already more than enough good reasons to not take up smoking. The growing popularity of vaping has provided fresh impetus, but also represents an opportunity for scientists. Research into the impact of nicotine on people’s health has long been held back by difficulties in isolating the effects of this one molecule from all the other components of cigarette smoke. “We never had a clean nicotine delivery product that would be used recreationally for long periods,” Goniewicz says. Now, thanks to e-cigarettes, researchers do.
This continuing population experiment, combined with a growing number of cell and animal studies, could begin to dissipate the fog surrounding nicotine’s impact on health. “I’ve been more and more surprised at the changes I’m seeing when I expose cells to nicotine,” says Crotty Alexander. “We’ve underplayed the role that nicotine has in the health effects of tobacco products.”