Clinical Pharmacology of Nicotine: Implications for Understanding, Preventing, and Treating Tobacco Addiction

Department of Medicine, University of California, San Francisco, California, USA.
Clinical Pharmacology &#38 Therapeutics (Impact Factor: 7.9). 05/2008; 83(4):531-41. DOI: 10.1038/clpt.2008.3
Source: PubMed


Understanding the basic and clinical pharmacology of nicotine provides a basis for improved prevention and treatment of tobacco addiction. Nicotine acts on nicotinic cholinergic receptors in the brain to release dopamine and other neurotransmitters that sustain addiction. Neuroadaptation and tolerance involve changes in both nicotinic receptors and neural plasticity. Nicotine addiction can occur in the context of physical dependence characterized by self-medication to modulate negative affect and/or to relieve withdrawal symptoms, as well as, in light or occasional smokers, primarily for positive reinforcement in specific situations. Nicotine is metabolized primarily by CYP2A6. Its clearance exhibits considerable individual variability that is determined by genetic, racial, and hormonal (sex) factors. Genetically slow metabolism of nicotine appears to be associated with a lower level of dependence. Nicotine dependence is highly heritable and appears to be influenced by genes coding for some nicotine receptor subtypes, some neurotransmitter genes, and genes involved in neural connectivity. Novel pharmacotherapies for nicotine dependence include partial agonists for nicotinic receptors and nicotine vaccines. Pharmacogenetic studies suggest various candidate genes and a nicotine metabolism phenotype that influence outcome. Human pharmacology studies of nicotine and smoking behavior also provide a basis for assessing the benefits and risks of long-term nicotine use for harm reduction and for a potential cigarette regulatory strategy that includes reducing nicotine content of cigarettes to nonaddictive levels.

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    • "While tobacco smoke contains ~4000 chemicals, of which ~250 are harmful, and ~50 are carcinogenic, nicotine itself is not a direct carcinogen [1] [21]. Nicotine may contribute to some smoking related diseases, but its contribution is generally considered much smaller than the tobacco combustion products, and NRTs do not increase the risk of cancer [22]. Notably, nicotine is contra-indicated in pregnant women because it may cause premature birth and in youths as it affects the developing brain [17]. "
    Asian Journal of Pharmaceutical Sciences 08/2015; DOI:10.1016/j.ajps.2015.07.004
    • "Smoking is motivated and maintained by nicotine (Benowitz, 2008), but smoking and craving are also influenced by situational stimuli (Kozlowski and Herman, 1984). Surveys reliably link smoking and craving to cues such as presence of other smokers and drinking alcohol (McKennell, 1970; Russell et al., 1974). "
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    ABSTRACT: Laboratory cue reactivity (CR) assessments are used to assess smokers' responses to cues. Likewise, EMA recording is used to characterize real-world response to cues. Understanding the relationship between CR and EMA responses addresses the ecological validity of CR. In 190 daily smokers not currently quitting, craving and smoking responses to cues were assessed in laboratory CR and by real-world EMA recording. Separate CR sessions involved 5 smoking-relevant cues (smoking, alcohol, negative affect, positive affect, smoking prohibitions), and a neutral cue. Subjects used EMA to monitor smoking situations for 3 weeks, completing parallel situational assessments (presence of others smoking, alcohol consumption, negative affect, positive affect, and smoking prohibitions, plus current craving) in smoking and non-smoking occasions (averaging 70 and 60 occasions each). Analyses correlated CR craving and smoking cue responses with EMA craving and smoking correlations with similar cues. Although some cues did not show main effects on average craving or smoking, a wide range of individual differences in response to cues was apparent in both CR and EMA data, providing the necessary context to assess their relationship. Laboratory CR measures of cue response were not correlated with real-world cue responses assessed by EMA. The average correlation was 0.03; none exceeded 0.32. One of 40 correlations examined was significantly greater than 0. Laboratory CR measures do not correlate with EMA-assessed craving or smoking in response to cues, suggesting that CR measures are not accurate predictors of how smokers react to relevant stimuli in the real world. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Drug and alcohol dependence 07/2015; 155. DOI:10.1016/j.drugalcdep.2015.07.673 · 3.42 Impact Factor
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    • "However, because NRTs appear to be more effective in suppressing tonic or background craving as opposed to phasic or peaks in craving (Ferguson and Shiffman, 2009; Schlagintweit et al., 2014), one might expect that NRTs would be most effective when smoking opportunities are not perceived to be imminently available. NRT effects are generally attributed to the pharmacological properties of nicotine M a n u s c r i p t 6 (e.g., Benowitz, 2008; Stead et al., 2012); however, there is growing evidence that suggests that non-pharmacological factors make a substantial contribution (Caggiula et al., 2001; Dar and Barrett, 2014). Balanced placebo research, which crosses instructions regarding nicotine content (told nicotine-containing vs. told nicotine-free) with actual nicotine content (contains nicotine vs. no nicotine) suggests that the belief that nicotine has been consumed reduces cigarette craving and withdrawal regardless of whether or not nicotine was actually consumed (Dar and Barrett, 2014; Darredeau and Barrett, 2010; Gottlieb et al., 1987; Schlagintweit et al., 2014). "
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    ABSTRACT: Background: Perceptions regarding the availability of smoking opportunities are known to affect cigarette craving; however, whether they impact actual smoking or how smokers respond to acute nicotine replacement therapy (NRT) administration is not known. This study examined the impact of pharmacological and expectancy components of NRT administration on craving and smoking in smokers anticipating or not anticipating an imminent smoking opportunity. Methods: In total, 154 smokers (84 male) completed an experimental session in which instructions regarding the nicotine content of a lozenge (4 mg vs. no nicotine) and regarding the availability of a future smoking opportunity were manipulated. Cigarette craving was assessed before and after manipulations and lozenge administration. All participants were then allotted 1h to self-administer as many cigarette puffs as they wished. Results: Unanticipated smoking opportunities reduced latency to self-administration (p<0.001), regardless of nicotine expectancy or pharmacology. When analyses included all participants, nicotine reduced intentions to smoke (p=0.016) and withdrawal-related craving (p=0.043) regardless of expectancy. Conversely, analyses using only "believers" of the nicotine content instructions revealed that nicotine expectancy reduced intentions to smoke (p=0.034) and withdrawal-related craving (p=0.047) regardless of actual nicotine administration. "Believers" also reported increased withdrawal-related craving when a smoking opportunity was perceived to be imminent (p=0.041). These effects were not significant when analyses included all participants. Conclusions: Findings suggest that unexpected smoking opportunities may be more appealing than expected ones regardless of perceived or actual acute NRT use. They also highlight the importance of reporting balanced placebo findings using all participants as well as "believers" only.
    Drug and alcohol dependence 02/2015; 147. DOI:10.1016/j.drugalcdep.2014.12.012 · 3.42 Impact Factor
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