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.

Smokers generally gain weight when they quit smoking; this weight gain can lessen some of the health benefits of quitting smoking. We review the effectiveness of behavioral and pharmacological approaches to mitigating weight gain in the context of quitting smoking and consider mechanisms that could potentially account for the effects of smoking and nicotine on body weight. Understanding how nicotine affects body weight may lead to novel pharmacological and behavioral interventions for obesity as well as concurrent obesity and nicotine dependence. Clinical Pharmacology & Therapeutics (2011) 90 1, 164–168. doi:

CYP2A6 is the main nicotine metabolizing enzyme in humans. We investigated the relationships between CYP2A6 genotype, baseline plasma 3HC/COT (a phenotypic marker of CYP2A6 activity), and smoking behaviors in African-American light smokers. Cigarette consumption, age of initiation, and dependence scores did not differ between 3HC/COT quartiles or CYP2A6 genotype groups. Slow metabolizers (both genetic and phenotypic) had significantly higher plasma nicotine levels suggesting cigarette consumption was not reduced to adjust for slower rates of nicotine metabolism. Individuals in the slowest 3HC/COT quartile had higher quit rates with both placebo and nicotine gum treatments (OR 1.85, 95% CI 1.08-3.16, p = 0.03). Similarly, the slowest CYP2A6 genotype group had higher quit rates, although this did not reach significance (OR 1.61, 95% CI 0.95-2.72, p = 0.08). 3HC/COT ratio, and possibly CYP2A6 genotype, may be useful in the future for personalizing the choice of smoking cessation treatment for African-American light smokers.

Advertisements suggest that smokers of cigarettes low in nicotine are exposed to less nicotine and tar. Nicotine yields are measured with smoking machines, but machines do not smoke cigarettes as people do. We therefore measured the actual nicotine content of commercial cigarettes with different nicotine and tar yields as determined with smoking machines, and also measured actual nicotine intake as indicated by blood concentrations of its metabolite, cotinine, in 272 subjects smoking various brands of cigarettes. We found that low-yield cigarette tobacco did not contain less nicotine; in fact, the nicotine concentration in tobacco inversely correlated (r = -0.53, P less than 0.05) with the concentration measured by smoking machines. Blood cotinine concentrations correlated with the number of cigarettes smoked per day but not with the nicotine yield measured by smoking machines. Only 3.8 to 5.0 per cent of total variance in blood cotinine was contributed by nicotine yield. We conclude that smokers of low-nicotine cigarettes do not consume less nicotine.

The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug-metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism.

The relationship between thermogenic and potentially atherogenic effects of cigarette smoking (CS) and its cessation was investigated. Heavy smokers (n = 7, serum cotinine > 200 ng/ ml, > 20 cigarettes/d) were maintained on isoenergetic, constant diets for 2 wk, 1 wk with and I wk without CS. Stable isotope infusions with indirect calorimetry were performed on day 7 of each phase, after an overnight fast. CS after overnight abstention increased resting energy expenditure by 5% (not significant vs. non-CS phase; P = 0.18). CS increased the flux of FFA by 77%, flux of glycerol by 82%, and serum FFA concentrations by 73% (P < 0.02 for each), but did not significantly affect fat oxidation. Hepatic reesterification of FFA increased more than threefold (P < 0.03) and adipocyte recycling increased nonsignificantly (P = 0.10). CS-induced lipid substrate cycles represented only 15% (estimated 11 kcal/d) of observed changes in energy expenditure. De novo hepatic lipogenesis was low (< 1-2 g/d) and unaffected by either acute CS or its chronic cessation. Hepatic glucose production was not affected by CS, despite increased serum glycerol and FFA fluxes. Cessation of CS caused no rebound effects on basal metabolic fluxes. In conclusion, a metabolic mechanism for the atherogenic effects of CS on serum lipids (increased hepatic reesterification of FFA) has been documented. Increased entry of FFA accounts for CS-induced increases in serum FFA concentrations. The thermogenic effect of CS is small or absent in heavy smokers while the potentially atherogenic effect is maintained, and cessation of CS does not induce a rebound lipogenic milieu that specifically favors accrual of body fat in the absence of increased food intake. (J. Clin. Invest. 1994. 93:265-272).

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References to other published versions of this review Gourlay 1997Gourlay SG, Stead LF, Benowitz NL. A meta-analysis of clonidine for smoking cessation. Cochrane Database of Systematic Reviews 1997, Issue 1. Gourlay 2001Gourlay SG, Stead LF, Benowitz NL. Clonidine for smoking cessation. Cochrane Database of Systematic Reviews 2001, Issue 4.