Karl Fagerstrom | 14 December 2013
We used to believe that nicotine is very dependence producing, but the evidence suggests that there are a number of problems with this statement. For example, animals do not self-administer nicotine as readily as they do other dependence producing drugs such as amphetamine, cocaine, and heroin (Villegier et al. 2003); nicotine is a relatively weak reinforcer in human laboratory studies (Perkins et al. 2001); abstinent smokers seem to prefer a much reduced or nicotine free e-cigarette rather than other - often stronger - nicotine-containing products like gum; and although nicotine replacement treatment is an effective aid for quitting smoking, its efficacy is moderate even in doses that replace most or all nicotine from the cigarettes formerly used (Dale et al. 1995). There is very little to no evidence for the abuse of nicotine when not delivered in a tobacco vehicle.
Dependence – a multi-component phenomenon
Dependence is a very complex phenomenon with behavioural, sensory, psychosocial, cultural and pharmacological aspects. The influence of some of these aspects becomes very clear when we look at the use of nicotine products compared with the use of tobacco. Pure nicotine, for example in nicotine patches, even in doses comparable to those of cigarettes, seems to have very little dependence potential and it is unheard of as an initiating product; cigarette smoking however, sometimes even when little smoke is inhaled, is very dependence producing. The explanation to this is partly that using a patch requires very little behaviour, gives poor control over dose, produces slow absorption of nicotine, has little or no sensory feedback, no conditioning of behaviour to external or internal stimuli, no social function and finally but not least, the patch does not contain other substances that likely contribute to the reinforcing effects of tobacco use and particularly smoking.
The role of other substances in tobacco
It has been known for some time that cigarette smoke inhibits monoamine oxidase (MAO) the enzyme that catalyses the metabolism of monoamine neurotransmitters, such as dopamine, thus potentiating their effects in the brain of smokers and thereby contributing significantly to reward and dependence. Nicotine is not directly responsible for this effect (Fowler et al., 1999). Acetaldehyde, an established constituent of tobacco smoke, is a potent inhibitor of MAO and it has been suggested that this compound causes the MAO inhibition. In experiments with rats, nicotine self-administration is enhanced when the animals are also treated with acetaldehyde. Other studies suggest that the condensation products of acetaldehyde, salsolinol, and the harmans are more likely candidates as the inhibitors MAO (Talhout et al 2007). Other tobacco-containing alkaloids, like myosmine, anatabine, anabasine and nornicotine, also seem to have rewarding effects in the sense that they substitute for nicotine in drug discrimination tests, and increase nicotine self-administration (Clemens, 2009).
When injections of nicotine were compared with injections of tobacco particulate matter in rats, it was found that injection of particulate matter was more reinforcing and produced a different reward profile than nicotine (Brennan et al. 2013).
If other constituents in smoked tobacco are also important in dependence, a consequence is that the term ‘nicotine dependence’ is often used incorrectly: it would be more accurate to refer to ‘tobacco dependence’ and even more precisely to ‘cigarette dependence’ when cigarettes are involved. Nicotine dependence is mostly studied in animals and more rarely in humans (Fagerstrom 2012).
Continuum of dependence
If one accepts that the possibility and difficulty of giving up tobacco and nicotine is a proxy or indicator for dependence, there is growing evidence that nicotine-containing products can produce different degrees of dependence. One way to investigate this is to look for evidence in the randomized placebo controlled trials listed in the Cochrane Library. The untreated controls are of particular importance here - ie those receiving placebo - because these can be used as a measure of how easy it is to stop using a nicotine containing substance without a treatment intervention. The results when stopping smoking show a long-term success rate in untreated controls of roughly 10% with little variation between studies. Those seeking to stop smokeless tobacco, but who are untreated have roughly more than double the success rate of cigarette smokers. A study of 69 long-term users (average 7 years) of pure nicotine, mostly in the form of nicotine gum, found a cessation rate of 36% in the untreated group (Tonnesen & Mikkelsen, 2012). There is also some evidence from the so called electronic cigarettes, which are better referred to as electronic nicotine delivery systems or devices, that users of them rate their dependence to them as less than that of cigarettes (Farsalinos et al. 2013).
As much as there is a continuum of harm with pure nicotine products on one end and cigarettes in the other, these studies suggest that it is easier to stop using some nicotine products than others and that there seems to be a continuum of dependence. This would place traditional cigarettes at one end and the pure nicotine products (and particularly nicotine patches) at the other end of the continuum (Fagerstrom& Eissenberg 2012).
Just as from a morbidity and mortality point of view, we would like to see users move away from cigarettes to less harmful products, the same can be true for dependence. One important reason for the unparalleled harmfulness of the cigarette is that users become so dependent on it. Fortunately it seems that the less harmful products, such as snus and the clean nicotine products, are also easier to give up. If the world could rid itself of smoked tobacco, particularly cigarettes, it would be easier to take further steps toward a nicotine free society if that would be desirable.
Dr Karl Fagerstrom, Sweden
Barrett, S. P. (2010). The effects of nicotine, denicotinized tobacco, and nicotine-containing tobacco on cigarette craving, withdrawal, and self-administration in male and female smokers. Behaviour Pharmacology, 21, 144–152. doi:10.1097/FBP.0b013e328337be68
Brennan, K., Crowther A., Putt F., Roper V., Waterhouse U., Truman P. Tobacco particulate matter self-administration in rats. Addiction Biology, doi:10.1111/adb.12099 [PDF]
Brody, A. L., Mandelkern, M. A., Costello, M. R., Abrams, A. L., Scheibal, D., Farahi, J., et al. (2009). Brain nicotinic acetylcholine receptor occupancy effect of smoking a denicotinized cigarette. International Journal of Neuropsychopharmacology, 12, 305–316. doi10.1017/S146114570800922X.
Clemens, K. J., Cailille, S., Stinus, L., & Cador, M. (2009). The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats. International Journal of Psychopharmacology, 12, 1355–1366. doi:10.1017/S1461145709000273]]
Cochrane Library. (2011). Pharmacotherapy interventions. Retrieved from
Dale, L. C., Hurt, R. D., Offord, K. P., Lawson, G. M., Croghan, I. T., & Schroeder, D. R. (1995). High-dose nicotine patch therapy. Percentage of replacement and smoking cessation. Journal of the American Medical Association, 274, 1353–1358. doi:10.1001/jama.1995.0353017003
Fagerstrom K. Determinants of tobacco use and renaming the FTND to the Fagerstrom Test for Cigarette Dependence. Nicotine Tob Res. 2012: 14; 75-78 [PDF]
Fagerstrom K & Eissenberg T. Dependence to tobacco and nicotine Products: A case for product specific assessment. Nic & Tob Res. 2012:14; 1382-1390. doi:10.1093/ntr/nts007 [PDF]
Farsalinos KE, Romagna G, Tsiapras D, Kyrzopoulos S, Voudris V. Evaluating nicotine levels selection and patterns of electronic cigarette use in a group of "vapers" who had achieved complete substitution of smoking. Subst Abuse. 2013 Sep 3;7:139-46. doi: 10.4137/SART.S12756
Fowler, J. S., Wang, G. J., Volkow, N. D., Franceschi, D., Logan, J., Pappas, N., et al. (1999). Smoking a single cigarette does not produce a measurable reduction in brain MAO B in non-smokers. Nicotine & Tobacco Research, 1, 325–329. doi:10.1080/14622299050011451
Perkins, K. A., Gerlach, D., Broge, M., Fonte, C., & Wilson, A. (2001). Reinforcing effects of nicotine as a function of smoking status. Experimental and Clinical Pharmacology, 9, 243–250. doi:10.1037/1064-12126.96.36.199
Tonnesen, P., & Mikkelsen, K. (2012). Varenicline to stop long-term nicotine replacement use: a double-blind, randomized, placebo-controlled trial.. Nicotine Tob Res. 2013 Feb;15(2):419-27. doi: 10.1093/ntr/nts146. Epub 2012 Sep 27
Villegier, A. S., Blanc, G., Glowinski, J., & Tassin, J. P. (2003). Transient behavioural sensitization to nicotine becomes long last¬ing with monoamine oxidase inhibitors. Pharmacology Biochemistry & Behaviour, 76, 267–274. doi:10.1016/S0091-3057(03)00223-5