Nicotine is so addicting that many people who are trying to become sober and smoke admit that it is far more difficult to break their nicotine habit, as shown in the following table:
| In terms of: | Relative rank: |
| Dependence among users | nicotine>heroin>cocaine>alcohol>caffeine |
| Difficulty achieving abstinence | (nicotine=alcohol=cocaine=heroin)>caffeine |
| Severity of physical withdrawal | Alcohol>heroin>nicotine>cocaine>caffeine |
| Intoxication | Alcohol>(cocaine=heroin)>caffeine>nicotine (because people will get nauseated before they reach intoxication levels. However, infants ingesting a pack of cigarettes will show toxicity.) |
| Deaths | Nicotine>>>alcohol>(cocaine=heroin); caffeine n.s. |
The typical mode of nicotine delivery, smoking, partially explains why nicotine is so addicting. In essence, each puff constitutes a separate “hit”, or bolus, that reaches the brain is less than 10 seconds. The average smoker takes 10 puffs from 36 cigarettes daily, thereby taking 360 separate and distinct hits of nicotine daily.
Molecular structure of nicotine, from Wikipedia commons. Its creator, Harbin releases its work into the public domain.
Its mode of action and its metabolism, together, provide a mechanism by which nicotine can be so addicting.
Mode of action
In the brain, nicotine preferentially binds to nicotinic acetylcholine receptors (nAChR) in the central and peripheral nervous systems. Nicotinic acetylcholine are a group of ion channels that are composed of five protein subunits bonded together. These subunits are subdivided into alpha, ‘a’, or beta, ‘b’ subtypes. In humans, 9 alpha subunits (a2 through a10) and 3 beta (b2 through b4) subunits have been identified. The binding affinities and electrophysiological properties of the receptors are determined by the specific combination of alpha and beta subunits.
Nicotinic acetylcholine receptors. From Wikipedia commons, This file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license. Author is Ataly, uploaded in 2009.
This binding of nicotine to its receptors on the postsynaptic cell induce the postsynaptic cell to fire, i.e. to produce an action potential. Among the cells that are affected downstream are those in the reward circuitry of the brain, thus explaining the onset of a pleasant sensation, which will disappear rapidly because nicotine is rapidly metabolized to cotinine in the liver. With the decline of nicotine blood levels, symptoms of withdrawal will be experienced, which can be unpleasant, including craving, irritability, restlessness, difficulty sleeping, feeling hungrier, or anxiety. The easiest way to avoid these unpleasant symptoms is to self-administer more nicotine.
Notice three important features of nicotine self-administration via cigarette via any of the other alternatives:
- The time to peak plasma concentrations with a cigarette is faster;
- The peak is higher with cigarette use;
- The drop is more precipitous with cigarette use than with any other modality.
These three features lead to a higher potential for addiction.
From pmiscience.com/en/smoke-free/nicotine/nicotine-and-addiction/
Both animal and human studies demonstrate that tolerance occurs very rapidly. For example, Lee et. al. (1987) compared the cardiovascular responses of human smokers to infused nicotine following a period of nicotine abstinence lasting either overnight or 7 days. They found that although heart rate and blood pressure responses were significantly greater after more prolonged abstinence, the blood concentration-effect relationships in the brief abstinence group approximated those of the longer-period abstinence group within 60 to 90 minutes.
The two most likely reasons for acute and chronic tolerance to nicotine are either an increase in the rate of drug metabolism, analogous to the induction of alcohol dehydrogenase levels in the liver following exposure to ethanol, or possibly a decrease in the sensitivity of tissues to nicotine. We do know that acetylcholine receptors become desensitized to nicotine with prolonged exposure.
In humans, the metabolism of nicotine is faster in smokers than in smokers (Kyerematen, et. al., 1982).
Metabolism
Cigarette smokers smoke an average of 36 cigarettes/day, and average daily intake of nicotine is 37.6 grams (Benowitz and Jacob, 1984). As tobacco smoke reaches the alveoli of the lungs, nicotine is rapidly absorbed and enters the bloodstream (Figure 11.2). The distribution half-life for nicotine is about 9 minutes. Eventually, measurable amounts of nicotine will appear in all body fluids, including saliva (Russell and Feyerabend, 1978), amniotic fluid and umbilical cord blood (Hibberd, et. al., 1978; Luck, et. al., 1982; Van Vunakis, et. al., 1974), breast milk (Hill and Wynder, 1979), and cervical mucous secretions (Sasson, et. al., 1985).
The elimination half-life of nicotine is about 2 hours. Relatively little of the nicotine is eliminated unchanged. Most of it is enzymatically converted in the liver to cotinine, and to a lesser extent, nicotine-N-oxide.
Smokers and non-smokers differ in the way they process and metabolize nicotine. Less than 10% of the nicotine injected into a non-smoker is converted into cotinine, while the corresponding amount for smokers is 25% (Beckett, et. al., 1971). Most cotinine will undergo further metabolism, but nicotine-N-oxide is excreted unchanged. The remaining nicotine and its metabolites are excreted in urine via glomerular filtration and tubular secretion.
Epidemiology
When we examine the prevalence of smoking, we find certain trends:
- The prevalence of smoking is higher in low-income and middle-income countries, compared to high-income countries;
- It is much higher among groups with lower levels of education or income and among those with mental health disorders and other co-addictions, which will be discussed a little further below. (Reference: Le Foll et. al., 2022);
- Smoking is more frequent among men than women;
As mentioned above, people with mental health disorders have a higher incidence of smoking. ”For example, the odds of smoking in people with any substance use disorder is more than five times higher than the odds in people without a substance use disorder. Similarly, the odds of smoking in people with any psychiatric disorder is more than three times higher than the odds of smoking in those without a psychiatric diagnosis…Comorbid disorders are also associated with higher rates of smoking (Le Foll et. al., 2022).”
The likelihood of nicotine addiction is inversely proportional to age of onset.
Smoking caused an estimated 7.7 million deaths globally in 2020, of which 80% were in men and 87% were current smokers.
Beckett, A.H.; Gorrod, J.W.; Jenner, P. (1971). The effect of smoking on nicotine metabolism in vivo in man. Journal of Pharmacy and Pharmacology 23(Supplement):62S-67S.
Benowitz, N.L.; Jacob, P., III. (1984). Daily intake of nicotine during cigarette smoking. Clinical Pharmacology and Therapeutics 35(4):499-504.
Hibberd, A.J.; O’Connor, V.; Gorrod, J.W. (1878). Detection of nicotine, nicotine-1’-N-oxide and cotinine in maternal and foetal body fuilds. In: Gorrod, J.W. (ed.) Biological Oxidation of Nitrogen. Elsever/North-Holland Biomedical Press, Amsterdam.
Hill, P.; Wynder, E.L. (1979). Nicotine and cotinine in breast milk. Cancer Letters 6:251-254.
Kyerematen, G.A.; Damiano, M.D.; Dvorchik, B.H.; Vesell, E.S. (1982). Smoking-induced changes in nicotine disposition: Application of a new HPLC assay for nicotine and its metabolites. Clinical Pharmacology and Therapeutics 32(6):769-780.
Le Foll, B.; Piper, M.E.; Fowler, C.D.; Tonstad, S.; Bierut, L.; Lu, L.; Jha, P.; Hall, W.D. (2022). Tobacco and nicotine use. Nature Reviews Diease Primers (2022) 8:19. https://doi.org/10.1038/s41572-022-00346-w.
Lee, B.L.; Benowitz, N.L.; Jacob, P., III. (1987). Influence of tobacco abstinence on the disposition kinetics and effects of nicotine. Clinical Pharmacology and Therapeutics 41(4):474-479.
Luck, W.; Hansen, R.; Steldinger, R.; Nau, H. (1982). Nicotine and cotinine—Two pharmacologically active substances as parameters for the strain on fetuses and babies of mothers who smoke. Journal of Perinatal Medicine 10(52):107-108.
Sasson, I.M.; Haley, N.J.; Hoffmann, D.; Wynder, E.L.; Hellberg D.; Nilsson, S. (1985). Cigarette smoking and neoplasia of the uterine cervix: Smoke constitutents in cervical mucus (Letter.) New England Journal of medicine 312(5):315-316.
Van Vunakis, H.; Langone, J.J.; Milunsky, A. (1974). Nicotine and cotinine in the amniotic fluid of smokers in the second trimester of pregnancy. American Journal of Obstetrics and Gynecology 120(1):64-66.
Addictions and Recovery 