• March 2, 2024

A Captivating Compound

 A Captivating Compound

The role of nicotine in tobacco harm reduction

By Grant Churchill

As a pharmacologist, I remain perplexed that most people, including scientists and doctors, are under the misconception that the harms of tobacco come from nicotine. Indeed, they believe that tobacco and nicotine are equivalent and that nicotine is carcinogenic. All not true. The thesis of this article is that the vast majority of the known harms of tobacco come from chemicals other than nicotine. Using the best current scientific evidence, I will first outline a few background concepts, including the scientific process, chemical terminology and a central concept of pharmacology. I will then cover the harms from tobacco and the harms from nicotine itself and compare them on a risk-benefit basis. I conclude that, based on the objective risks, nicotine is an excellent option for achieving tobacco harm reduction.

Another common misconception is that science is a list of facts. Science is a process in which there is never absolute proof but rather a continuum of probabilities of belief. As Benjamin Disraeli said, “When the evidence changes, I change my mind, what do you do?” Therefore, if the scientific evidence changes, the conclusions of this article will also change. The experimental evidence also has degrees of strength and is often debatable and controversial, especially where results from studies using isolated chemicals on cells and animals in the lab are extrapolated to humans.

In common parlance when we say something contains “chemicals,” it means artificial additives or synthetic compounds and comes with a negative connotation. Moreover, “organic” is taken to mean natural, no additives and “chemical-free,” which is impossible as everything is made up of chemicals, including us humans. Often, “synthetic” is associated with toxic and “natural” with harmless. From a pharmacologist’s point of view, a chemical is never given a binary classification of toxic or nontoxic but has a degree of harm related to the dose, as stated by Paracelsus that “the dose makes the poison,” which forms a central concept in pharmacology. So, stating that nicotine is toxic, in a certain sense, is very true, but so is water, as about 4 liters will kill a person. Conversely, botulinum toxin is both natural and one of the most toxic substances known, yet it is used safely at low doses for removing wrinkles. The proper question is not whether nicotine is toxic but rather: What is the exposure dose relative to the toxic dose?

With the above as background, I now address the relationship of nicotine to tobacco through the lens of harm reduction. In terms of epidemiological data, smoked tobacco carries extensive harms in terms of cancers, lung disease and lost lives and shortened life expectancy. As a pharmacologist, it is patently obvious that tobacco, especially smoked tobacco, is not nicotine and that nicotine is not tobacco. As professor Michael Russell stated, “People smoke for nicotine, but they die from the tar.” Definitions vary, but tar is particulate matter made up of a very complicated mix of only partially known chemicals. Indeed, tobacco smoke is estimated to contain up to 7,000 chemicals, and around 100 are known toxins and/or carcinogens at exposure levels experienced by smokers.

Most of the harmful chemicals form when tobacco burns (combustion). During combustion, tobacco provides the fuel in the form of chemicals composed mainly of linked carbon and hydrogen (akin to the chemical cellulose in wood fueling a log fire) that split apart and combine with oxygen to form carbon dioxide and dihydrogen oxide (water!). Total conversion is complete or clean combustion, but tobacco combustion is incomplete and results in carbon monoxide rather than dioxide and soot and tar, which are carbon-based chemicals created by the heat, which facilitates a process whereby the bonds that hold atoms together are rearranged to produce a bewildering complex array of new chemicals.

One major class of chemicals in tar is polyaromatic hydrocarbons, which are large, flat molecules composed of six-membered rings (chicken wire) that insert between the stacked bases of DNA and cause errors when it replicates. Some chemicals are volatile organic compounds, such as aldehydes (formaldehyde and acetaldehyde), which are highly chemically reactive and modify DNA bases. Changes in DNA bases result in mutations, the genetic equivalent of spelling mistakes, and can cause cancer. Other harmful volatile chemicals have acute effects, such as carbon monoxide, which displaces oxygen from hemoglobin in blood.

Some of these so-called toxic chemicals in tobacco smoke are natural metabolites produced in our bodies enzymatically, such as carbon monoxide and formaldehyde. All aldehydes are highly reactive and can be harmful, including glucose, but in low amounts, those produced or consumed are detoxified through metabolism. This further illustrates that it is not the chemical or its origin (natural or synthetic) but the dose that makes the poison. From an evolutionary perspective, we evolved consuming many toxic chemicals from our environment and have methods to detoxify and excrete these. Tobacco smoke is exceptionally harmful not due to the presence of a given chemical but crucially the dose to which a smoker is exposed.

It seems perverse for humans to smoke, that is, to create a large and unknown mixture of chemicals through burning and then inhale them. Yet, humans have inhaled the smoke from plant material for millennia and continue to do so to get a fast rush from psychoactive drugs in them. It is interesting to examine the possible origins of this behavior. It has been suggested that this began with the use of fire to cook our food, which destroys pathogens and toxins, and the use of smoke, which preserves food from microbial spoilage. Evolutionarily, fire and smoke had health benefits over the short term (to enable us to pass on our genes through reproduction), but evolution does not select against long-term harms. We are the products of this evolutionary pressure and have a strong preference for the charred and caramelized flavors and “tobacco” notes in food and drink. Unfortunately, the desirable aromas and flavors are part of a large mixture of chemicals formed upon combustion, so with the antimicrobial chemicals also come, most unfortunately, irritants and carcinogens.

The discussion above outlines why tobacco, particularly when burned, is harmful, but what about nicotine itself? Theoretically, nicotine could be harmful based on its chemical reactivity as carcinogens such as nitrosamines modify DNA or through pharmacological means with nicotine interacting with its biological target, the nicotinic acetylcholine receptor. Nicotine itself is unreactive, and although metabolic reactions in the body in the liver oxidize it and can make it into reactive metabolites, the dose is very low and not considered meaningful. Nicotine is commonly thought to be a carcinogen, but there is no scientific evidence supporting this. In some literature, the term “cancer promoter” has been conflated with carcinogen. In some studies, with cells in the lab, nicotine has been shown to be a cancer promoter. Promoters are compounds that stimulate cell growth and sensitize cells to chemical carcinogens that damage DNA. Any substance that enhances cell growth can potentially be a cancer promoter, such as glucose or even certain vitamins. So, while technically true in cells in culture, in intact humans, there is no evidence that this is a concern, and nicotine is not considered a carcinogen. These data illustrate a specific challenge in studying the potential effects and harms of nicotine as much of the research into the potential harms of nicotine comes from studies in cells and animals where the doses used are often very high, leading to results that are controversial and difficult to extrapolate to humans.

Do the pharmacological effects of nicotine on the three subtypes of its receptor result in any toxicity? For acute toxicity, the lethal dose is between 60 mg and 600 mg (30 cigarettes to 300 cigarettes), with toxicity resulting from stimulation of the least sensitive subtype of receptor (neuromuscular) that is present on nerves that stimulate skeletal muscle. The most sensitive subtype are the brain receptors, which elicit the cognitive and mood effects of nicotine and have been suggested to underlie neurological developmental problems, but the data are correlative rather than causal. The third receptor subtype (ganglionic) resides in nerves controlling the “flight or fight” adrenaline response and mediates the most investigated and substantiated potentially harmful effects of nicotine per se and give rise to cardiovascular effects. For example, nicotine has been shown to increase blood pressure, heart rate and cause blood vessels to become atherosclerotic. However, the effects are not large and are currently not considered a concern except possibly for those with cardiovascular disease. Indeed, professor David Nutt has noted that the size of the effect is similar to watching a scary movie.

The disconnect between the cellular/animal studies and human studies is not unique to nicotine and has been well documented for bacon, coffee and even vegetables. In bacon cured with nitrate salts, cooking results in the formation of nitrosamines, which are highly carcinogenic in rats but not humans because humans metabolize nitrosamines differently than rodents. In humans, there is an epidemiological risk from eating bacon, but it is far less than suggested by the rodent studies. Roasted coffee beans contain 826 volatile chemicals, and of the 21 tested, 16 are rodent carcinogens, but, paradoxically, drinking coffee has health benefits in the human population. Professor Bruce Ames’ work has shown that many chemicals from vegetables test positive in rodent carcinogenicity tests, but consuming vegetables in our diets is protective, illustrating that the results from individual chemicals at high concentrations cannot be reliably extrapolated to their effect on humans. The take-home message from these studies is that human epidemiological data are the ultimate test and trump any lab-based results, be they on DNA, cells or animals. Overall, the well-conducted studies that can separate the effects of nicotine from those of other chemicals, such as in tobacco smoke, have revealed minimal effects and harms from nicotine itself, but this area remains controversial.

In regard to nicotine, the most informative studies are those done in humans. Somewhat ironically, the best evidence for the effects of nicotine itself come from use of a particular form of tobacco called snus. Snus is used in a packet placed between the gums and lips, and nicotine is absorbed through oral mucosal membranes. Snus is not burned nor does it contain high amounts of nitrosamines, which are carcinogens present in unburned tobacco at amounts dependent on the drying and curing process. If snus use were associated with health harms, it would be impossible to disentangle the chemical cause being nicotine or another chemical. Specifically, prevalence statistics and epidemiological data indicate that the use of snus confers a significant harm reduction benefit, which is reflected in the comparatively low levels of tobacco-related disease in Sweden when compared with the rest of Europe. The available scientific data, including long-term population studies conducted by independent bodies, demonstrates that the health risks associated with snus are considerably lower than those associated with cigarette smoking. By extension, one can infer minimal or no harm with nicotine use. But, as you might have guessed, interpretation of these data is controversial.

To conclude, in regard to tobacco harm reduction, the question is not whether nicotine has any harm but rather how harmful is nicotine relative to tobacco. Given that tobacco smoke is exceptionally harmful, anything that can reduce smoking will have health benefits to both the individual and society. Nicotine, the chemical itself, is addictive, but from a pharmacological perspective, when used as intended through properly regulated means, the balance of evidence shows that it has minimal harm. Therefore, nicotine is an excellent means for tobacco harm reduction as it can combat smoking, the largest cause of preventable deaths worldwide.