Nicotine is an addictive substance; it is THE addictive substance in tobacco, although tobacco’s combustion products are responsible for most of its adverse health effects. Nicotine has been in the news a lot between the plan to remove JUUL, a nicotine delivery system from the market, and the FDA proposal to require cigarettes to have lower nicotine levels. I asked myself a simple question for which I did not have a ready answer, what amount of nicotine is necessary to get you addicted – what dose makes the poison?
The decision by the FDA to require lower nicotine levels in cigarettes is predicated on the idea that by lowering the dose sufficiently, a non-addictive cigarette could be created. What scientific evidence do we have on what that nicotine dosage might be? To find an answer, I looked at a nicotine review from 2012. Here is what I found.
The Family Smoking Prevention and Tobacco Control Act (FSPTCA), passed in 2009, gives the FDA the authority to reduce but not eliminate nicotine from tobacco products. This involved “denicotinization” of tobacco, reducing the amount of nicotine, either by chemical extraction or through modified tobacco crops. It is not a “light” cigarette, which reduces nicotine by placing small ventilation holes in the filter – which has never been shown to reduce nicotine, and this labeling is banned in the US. As the decline in smoking through the current regulations and taxations seem to be “hitting a wall” (declining from 19% to 14% between 2010 and 2018), regulators seeking a science-informed approach have focused on identifying a nicotine-addiction threshold.
Nicotine’s Addiction Threshold
Cigarettes contain between 1 and 1.5mg of nicotine, a variable amount of which will be delivered to the smoker’s bloodstream based upon how deeply and frequently they inhale. Invasive studies using multiple blood samples have demonstrated that smokers maintain nicotine levels between 10-50 ng/ml. Similarly, other blood sample studies rely on cotinine, a non-addictive, metabolic byproduct of nicotine that acts as a biomarker of nicotine levels. More often, to avoid blood sampling altogether, the marker of nicotine levels is the number of cigarettes smoked.
Studies of “chippers,” individuals who smoke intermittently or just a few cigarettes, have identified a blood level of cotinine of 50 ng/ml, nicotine’s biomarker. Chippers smoke roughly five cigarettes (therefore 5 mg of nicotine) daily, and researchers have concluded that a cigarette with 0.17 mg of nicotine would be below an addiction threshold. It is readily apparent that this is, at best, an approximation.
A larger question is wrapped within the term “addiction threshold.” What do we mean by addiction? There is no clear line between “dependent and nondependent smokers.” Some researchers rely on DSM-V criteria , others on the Fagerström Test for Nicotine Dependence (FTND) scale . Unfortunately, there is no clear correlation between these two addiction criteria, and “there is still no consensus on what represents the most reliable and valid method for assessing nicotine addiction.”
Nicotine’s Reinforcement Threshold
Adding to the ambiguity of definitions is the concept of nicotine reinforcement – “the lowest nicotine dose that will increase or maintain nicotine self-administration behaviors.” Reinforcement is more easily measured because it involves short-term studies, whereas establishing dependence requires longer time frames. Given the difficulties with identifying a nicotine addiction target, these researchers believed that the reinforcement threshold would be a more science-based, objective target for regulation.
Studies of a reinforcement threshold have their limitations. Because smoking delivers variable amounts of nicotine, most studies have employed pure nicotine delivered either as a nasal spray or intravenously – not exactly replicating the individual and social interactions, e.g., that first cigarette with a cup of coffee or the cigarette break at work, that may be part of tobacco’s addictive nature. Studies using nasal spray have not demonstrated a reinforcement threshold.
Intravenous studies provided additional insight. First, reinforcement was time-mediated; a reinforcing dose, more efficiently delivered intravenously, produced a “rush.” Think of that first puff, long and deep. Second, after a host of studies, there was general agreement that the “ballpark” dose of reinforcing nicotine was between 1.5 and 6.0 µg/kg. But even that range comes with caveats, including the need to identify genetic, gender, or ethnic differences, the possibility that cigarettes contain other substances that facilitate nicotine levels (for example, menthol), and determining how well a reinforcement threshold predicts long-term use.
How would a low nicotine cigarette affect public health?
We should also consider the rationale behind the reduction in nicotine levels. Do new smokers seek a nicotine addiction or some type of social acceptance from their peers? As a professor of health psychology wrote:
“Experimenting with smoking usually occurs in the early teenage years and is driven predominantly by psychosocial motives. For a beginner, smoking a cigarette is a symbolic act … Children who are attracted to this adolescent assertion of perceived adulthood or rebelliousness tend to come from backgrounds that favour smoking …. [and] also tend not to be succeeding according to their own or society's terms …”
Theoretically, if a non-addictive dosage were identified, these cigarettes would no longer be chemically addictive. New smokers would be protected from the chemical addiction that reinforces the social behavior and might more easily stop.
Would a lower nicotine dose help these new smokers and those already smoking quit? The two biggest advocates of lowering nicotine levels reported on three such studies. In each study, lower nicotine cigarettes resulted in lower nicotine levels, and “some smokers quit smoking spontaneously, and those who continued to smoke reported a lower level of dependence.” Nor did these smokers increase the number of cigarettes they smoked to achieve a higher nicotine level. This suggests that none of these amounts, as low as 0.05 mg of nicotine/cigarette, were below nicotine’s reinforcement level. More importantly, the researchers felt cigarette use did not increase “because of the satiating effect of the tar, chemical irritants and related taste, the levels of which were unchanged in reduced nicotine content cigarettes.” Let me restate this, low-nicotine cigarettes reduced nicotine but did not have any impact on the combustion products associated with cancer – an unintended consequence, at least if we do not consider the scientific data we already have.
The FDA’s proposal to reduce the nicotine in cigarettes has been kicking around for years. The only change was that a proposal will be put forth for public comment next year. Those comments will usher in a contentious debate between tobacco companies and advocates of smoking cessation – we need only consider the recent menthol ban as a harbinger of things to come.
Deliberately inhaling hot gases containing combustion products is stupid and will adversely impact your health. Reducing the nicotine level in cigarettes sounds like a good idea, but what we know about nicotine so far argues that these theoretical low-nicotine cigarettes are not likely to be helpful to current smokers. Whether it might lessen the possibility that a new smoker continues is unknown. Putting the toothpaste back in the tube is difficult, and we should be wary of solutions that sound good but make uncertain assumptions.
 To paraphrase tobacco use disorder manifests two or more of these symptoms.
- Persistent desire or unsuccessful attempt to control tobacco use, including greater amounts or longer periods of usage
- Recurrent tobacco use results in failed obligations at work, school, or home. Persistent use despite social or interpersonal problems, e.g., arguments or missed social duties, exacerbated by tobacco use
- Tobacco use when it is physically hazardous
- Continued use despite knowing it has a deleterious effect on your health, physical or mental.
- Tobacco tolerance by either using increased amounts or experiencing diminished effects from current amounts.
- Symptoms of tobacco withdrawal
 Fagerström Test for Nicotine Dependence consists of six questions about cigarette use, compulsion, and dependence. On a 1 to 10 scale, higher is more dependent.
Source: The Reinforcement Threshold for Nicotine as a Target for Tobacco Control Drug and Alcohol Dependence DOI: 10.1016/j.drugalcdep.2012.04.02