Nicotine 101: The Truth About What It Is and What it Does

    In July 2017, an announcement by the FDA declared that the agency “places nicotine, and the issue of addiction, at the center of the agency’s tobacco regulation efforts.”

    It’s no surprise that with this renewed focus on nicotine—and ensuing FDA-driven fear-mongering surrounding products that contain the substance, even if they don’t involve combustion of tobacco—people are more confused than ever about what nicotine is and what it does.

    Does it cause cancer? Will smoking a cigarette or vaping instantly make you addicted? Does it cause brain worms?

    Spoiler: No, no and unlikely.

    Surely both the Food and Drug Administration and lawmakers should answer such questions accurately before going forward with policies that are likely to dissuade people from replacing combustible cigarettes with reduced-risk nicotine products?


    What Nicotine Is and What it Does

    Nicotine is naturally occurring chemical derived from plants of the nightshade family—which include tobacco, but also foods like tomatoes, potatoes and eggplant.

    Though often thought of as a bad guy, nicotine itself is actually fairly safe. As with most substances, there is a lethal dose of nicotine, but the exact lethal dose is largely undetermined—in part because there are no realistic circumstances in which we would inadvertently encounter it.

    Based on studies from a variety of species, the potential lethal dose for a human has generally been estimated at 60 milligrams or less, if taken all at once, although data indicate that 500mg of oral nicotine would be required to kill a human adult. Fatal nicotine poisonings are extremely rare. The average cigarette contains between 7-14mg of nicotine (much of that is not inhaled) and average consumption for smokers over the course of a day is 38mg (80mg at the highest end of the spectrum). There are reports of people surviving even extremely high doses of nicotine ingestion, including one of up to 4 grams of pure nicotine. This is likely due to nicotine causing vomiting quickly after ingestion, which prevents its uptake in the blood.

    Nicotine works by binding to and activating nicotinic receptors in our bodies. We naturally produce a neurotransmitter called acetylcholine (ACH), which activates two distinct types of ACh receptors in our bodies: fast-acting nicotinic receptors (nACh), named because they are sensitive to nicotine; and slower-acting muscarinic receptors (mACh), named because they are sensitive to muscarine, another naturally occurring substance, found in mushrooms.

    Both types of receptors play a role in our bodies’ nervous system. Untouched by outside chemicals, the nicotinic and muscarinic receptors work together to maintain balance, or homeostasis, between the body’s “fight or flight” response—primarily driven by the nicotinic receptor—and its “rest and digest” response, which is primarily driven by the muscarinic receptor.

    When an outside chemical like nicotine is added, the scales are tipped, changing homeostasis. However, our bodies are amazingly adept at resetting homeostasis to maintain balance—in this case, the balance may be reset by decreasing or deactivating nicotinic receptors in response to a large influx or chronic exposure to the drug.

    When it is taken orally, the effects are subtler—which is why people generally gravitate toward inhalation.

    Changes in the way nicotine is consumed can lead to different results. Nicotine is most rapidly absorbed, and therefore has its most powerful effects in the brain, when it is inhaled. When it is taken orally, the effects are subtler—which is why people generally gravitate toward inhalation rather than consuming nicotine through other routes, such as chewing tobacco or nicotine gum.

    Yet whether inhaled or chewed, when nicotine binds to the body’s nicotinic receptors, it affects dopamine release in the areas of the brain that process reward (more on that later).

    But what about the consequences of long-term nicotine use?

    Once upon a time, the FDA did not approve long-term use of nicotine replacement therapies, urging people to completely quit all forms of nicotine within a maximum of 12 weeks.

    More recently, the agency has walked back those recommendations after realizing that long-term nicotine use is rather benign, and if nicotine replacement therapies can mitigate the risk for relapse to smoking, then continuing to use nicotine as a replacement therapy is better than an abstinence-only approach.

    While the FDA has an eye to restrict vaping, a landmark study recently indicated that e-cigarettes are about twice as effective for smoking cessation as non-inhaled nicotine replacement therapies—a finding that chimes with the higher effectiveness of nicotine when it is inhaled.

    Nicotine may exacerbate hypertension, but it is not responsible for the hardening of arteries, cancer or emphysema.

    The health problems that are popularly associated with long-term nicotine useincluding heart disease, various forms of cancer and stroke, to name a fewlargely arise from smoking combustible cigarettes.

    When not accompanied by tar, carbon monoxide and the myriad chemicals associated with combustible tobacco, nicotine may exacerbate hypertension, but it is not responsible for the hardening of arteries, cancer or emphysema.

    So if nicotine does not cause cancer, heart disease or lung diseasebut its use in isolation helps millions of people to avoid the combustible cigarettes that do cause these diseases, and indeed, as we’ll see, even has inherent benefits—then what’s the problem?


    Why Public Health Agencies Are Worried About Nicotine Use

    The FDA and other public health agencies concerned with nicotine use have taken to highlighting how it affects the brain—specifically the areas associated with reward and stress systems that mediate addiction. It is with these effects that nicotine’s use becomes both a practical and moral quandary.

    Nicotine affects our brains—that cannot be denied. And the fact that nicotine increases dopamine transmission in the brain’s reward centers might cause longer-term—but not permanent—consequences, such as increasing reward thresholds (which leads to dissatisfaction or depression in the absence of nicotine) and altering our stress responses (resulting in anxiety and irritability during abstinence).

    A typical smoker goes through several withdrawal cycles a day—followed by increases in stress hormones and heightened stress response. It is with this emerging adaptation that a state of addiction is believed to arise.

    Nicotine also produces a common dependence syndrome: withdrawal.

    While never an enjoyable experience, the dangers and discomforts of nicotine withdrawal rarely conform to the popular cultural portrayal of withdrawal symptoms. One interesting aspect of nicotine withdrawal is that the somatic, or bodily, withdrawal symptoms (including possible low blood pressure, an abnormally slow heart and intestinal distress) are quite weak compared to the psychological symptoms, which include irritability, anxiety, depressed mood, craving and malaise.

    This is likely due to the fact that during nicotine withdrawal, the brain’s reward thresholds become elevated, meaning that more stimulus is required to produce the same reward during withdrawal than would otherwise be required. In other words, after abstaining from nicotine for a period of time, nicotine users experience a diminished sense of enjoyment from all rewarding stimuli. These effects far outlast the somatic withdrawal symptoms and encourage people to continue using nicotine products.

    How does all of this happen? As with any rewarding stimuli, it is the “binge” and “withdrawal” cycles that are largely responsible for the emergence of the brain’s adaptations.

    A typical smoker goes through several withdrawal cycles a day—usually during working and sleeping hours. These cycles are followed by increases in stress hormones and heightened stress response. It is with this emerging adaptation that a state of addiction is believed to arise, which may affect everything from attention to impulse control to mood. This may sound scary—and is probably a reason why people associate addiction, or the associated agents that bring about these changes, with brain damage. But brain changes aren’t brain diseases, and it’s rare that reinforcing drugs cause brain damage—it’s more common with toxic doses of amphetamine or amphetamine-like drugs that result in neuronal death.

    Of course, we are not rats, and rats do not experience all the things humans do—poverty, wealth, isolation, social support or even variations in diet, to name a few.

    Does nicotine always cause these effects? Probably not. When taken orally, nicotine does not affect the brain with the same intensity as it does when it is inhaled. Additionally, people have different experiences that may affect the way the brain reacts to rewarding stimuli—including transitioning from use to addiction. This transitioning phase, rightly or not, is a major concern for our public health agencies.

    However, what we know about differential activation of brain reward and stress systems is primarily from animal studies. These are useful because, in a controlled environment, animal studies provide a common baseline for scientists to track and evaluate alterations in the brain.

    But the consequences of these alterations are not as clear-cut as they may seem. And of course, we are not rats, and rats do not experience all the things humans do—poverty, wealth, isolation, social support or even variations in diet, to name a few. And with so many views of addiction, outside of a purely neurobiological model, it is difficult to discern what bearing any of this information has.


    So Is Nicotine Addictive?

    There is wide disagreement over whether nicotine per se is addictive. To begin, there are at least four separate, commonly referenced views of addiction:

    The psychiatric view: Addiction has aspects of an impulse control disorder (taking something for pleasure) and a compulsive disorder (taking something to relieve stress).

    Psychodynamic view: Addiction is the result of developmental difficulties, emotional disturbances, structural factors, personality organization and a dysfunctional view of “self.”

    Social psychology view: Addiction is the result of poor self-regulation.

    Dependence view of addiction: Addiction is the result of an abnormal state where administration of a drug is required to maintain physiological equilibrium.

    As is often the case, some combination of these theories—along with others not mentioned here—is likely the most accurate way to define addiction right now. This is especially true when we consider the ever-changing social acceptability of certain drugs and behaviors, not to mention the legal, physiological and personal consequences that must be specifically considered for each.

    One persuasive criterion for addiction—reflected, for example, in the American Psychiatric Association’s definition for substance use disorders—is that significant harms are associated with drug-seeking or taking.

    Among researchers, physicians and harm reduction advocates, most agree that cigarettes are associated with addiction—whether because they define addiction by high relapse rates, increases in physiological dependence, the inclusion of psychoactive chemicals found in combustible tobacco, or the continuance of smoking despite clear health dangers.

    But is taking nicotine that is not in the form of a cigarette a result of poor self-regulation? Or worse yet, brain damage? The answer largely depends on who you ask.


    What Does This All Mean?

    Initially, the FDA’s decision to reframe the public health interests from smoking to nicotine held some promise. Recognizing that the combustible cigarette, rather than nicotine, is the leading cause of preventable death in the United States could have blazed a trail for tobacco harm reduction and pushed tobacco companies that primarily sell products that kill to invest in products that do not.

    Neither the benefits nor the  consequences of nicotine use need to be exaggerated for the good of public health.

    Yet as unlikely as this new utopia may have seemed at the time, the FDA has since made achieving it downright impossible, with its constant attempts to force down the public’s throat the idea that nicotine is inherently damaging.

    The reality is that nicotine isn’t scary—in fact, its benefits are well-documented: It increases attention span and concentration, can increase physical performance and prevent fatigue, and can elevate mood. Sure, it affects the brain in positive and negative ways, but that can truly be said of everything we do.

    It’s easy to argue that poor regulatory policies are to blame for the upside-down world we live in, where more dangerous products are protected and far safer ones are facing extinction.

    However, we cannot overlook the fact that the rhetoric and misinformation surrounding nicotine is scaring the pants off people who could benefit from safer forms of the drug— the forms that are more likely to result in successful quitting of cigarettes.

    Neither the benefits nor the consequences of nicotine use need to be exaggerated for the good of public health. Perhaps the first step to understanding nicotine and, in turn, to ensuring that any necessary regulations do not exacerbate public health harms, is to simply have a normal, honest dialogue.

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    • Carrie Wade, PhD, is a senior fellow and the harm reduction policy director for the R Street Institute, where she is responsible for directing R Street’s harm reduction agenda, including opioids, tobacco and sexual health.

      She previously worked as a drug researcher at the University of Minnesota and the Scripps Research Institute in La Jolla, California. She received her bachelor’s in Neuroscience and PhD in Pharmacology from the University of Minnesota, and a master’s in Public Health from Johns Hopkins University.

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