6.11Tolerance, dependence and withdrawal

Last updated: January 2018

Suggested citation: Christensen, D. 6.11 Tolerance, Dependence, and Withdrawal.  In Scollo, MM and Winstanley, MH [editors]. Tobacco in Australia: Facts and issues. Melbourne: Cancer Council Victoria; 2018. Available from http://www.tobaccoinaustralia.org.au/chapter-6-addiction/6-11-tolerance-dependence-and-withdrawal

Nicotine tolerance results from adaptation to the effects of nicotine where responses diminish or fall after repeated nicotine consumption, or where greater nicotine dosages are required to achieve the same magnitude of response.1 Typically, compared to non-smokers, smokers report less severe aversive subjective effects (nausea, headache, etc.) than non-smokers who were given the same dose of nicotine, although these differences might be attributable to chronic drug exposure rather than smoking status.2 However, non-dependent smokers are typically similar to dependent smokers on a range of acute cardiovascular measures,2 indicating that although these groups differ in their dependence, they share common tolerance effects. Further, chronic tolerance declines very little during abstinence, suggesting chronic tolerance is not closely related to dependence.2

Nicotine dependence is indicated by repeated unsuccessful efforts to stop smoking, experiencing withdrawal symptoms when attempting to stop smoking, smoking despite experiencing health problems, and giving up social or recreational activities in order to smoke, among other criteria (See Section 6.1). The evidence suggests a weak relationship between nicotine tolerance and dependence. However, there is a stronger association between withdrawal effects (e.g., anxiety, depression, trouble sleeping, etc.) and dependence, where avoidance of nicotine withdrawal is a common reason reported by smokers to continue smoking.3 Moreover, some research suggests nicotine dependent smokers have reduced responsiveness to pleasure from other sources.4, 5 This reduction in pleasure and pleasure seeking further increases risk of abstinent smokers relapsing, as other compensatory behaviours are less appealing during withdrawal.3

Nicotine withdrawal is characterised by a range of effects during abstinence including severe craving for nicotine and/or tobacco, feelings of irritability, anxiety, anger, difficulty in concentrating, restlessness, impatience, increased appetite, weight gain, and insomnia.6 Typically, symptoms begin a few hours after smoking cessation, peak within two days to a week, and then decline over the next two or several weeks.67 Additional factors include persistent mild depression and increased appetite.6 Further, some researchers suggest the severity of nicotine withdrawal is unrelated to smoking frequency, length of smoking history, previous quit attempts, or demographic variables; factors often related to withdrawal symptoms from other drugs of abuse.7


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1. American Psychiatric Association, Diagnostic and statistical manual of mental disorders.  5th ed Arlington, VA: American Psychiatry Association; 2013.

2. Perkins KA. Chronic tolerance to nicotine in humans and its relationship to tobacco dependence. Nicotine & Tobacco Research, 2002; 4(4):405–22. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12521400

3. Frandsen M, Thorpe M, Shiffman S, and Ferguson S. A clinical overview of nicotine dependence and withdrawal, in Negative affective states and cognitive impairments in nicotine dependence.  Hall S, Young JW, and Der-Avakian A, Editors. San Diego: Academic Press; 2017.

4. Pergadia M, Der-Avakian A, D’Souza M, Madden P, Health A, et al. Association between nicotine withdrawal and reward responsiveness in humans and rats. JAMA Psychiatry, 2014; 71:1238–45. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25208057

5. Pizzagalli DA, Jahn AL, and O'Shea JP. Toward an objective characterization of an anhedonic phenotype: A signal-detection approach. Biological Psychiatry, 2005; 57(4):319–27. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15705346

6. Advocat C, Comaty J, and Julien R, Julien’s primer of drug action.  13th ed New York: Worth Publishers; 2014. Available from: http://www.ncbi.nlm.nih.gov/nlmcatalog/101666863.

7. McKim W and Hancock S, Drugs and behaviour: An introduction to behavioural pharamacology.  7th ed New York: Pearson; 2013.


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