Neal L Benowitz

San Francisco VA Medical Center, San Francisco, California, United States

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Publications (607)4602.75 Total impact

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    ABSTRACT: Aims: To measure the systemic retention of nicotine, propylene glycol (PG), and vegetable glycerin (VG) in electronic cigarette (e-cigarette) users, and assess the abuse liability of e-cigarettes by characterizing nicotine pharmacokinetics. Design: E-cigarette users recruited over the Internet participated in a 1-day research ward study. Subjects took 15 puffs from their usual brand of e-cigarette. Exhaled breath was trapped in gas-washing bottles and blood was sampled before and several time after use. Setting: San Francisco, California, USA. Participants: Thirteen healthy, experienced adult e-cigarette users (6 females and 7 males). Measurements: Plasma nicotine was analyzed by GC-MS/MS, and nicotine, VG, and PG in e-liquids and gas traps were analyzed by LC-MS/MS. Heart rate changes and subjective effects were assessed. Findings: E-cigarettes delivered an average of 1.3 (0.9-1.8) mg (mean and 95% CI) of nicotine and 94% of the inhaled dose, 1.2 (0.8-1.7), was systemically retained. Average maximum plasma nicotine concentration (Cmax ) was 8.4 (5.4-11.5) ng/mL and time of maximal concentration (Tmax ) was 2 to 5 minutes; one participant had Tmax of 30 minutes. 89% and 92% of VG and PG, respectively, was systemically retained. Heart rate increased by an average of 8.0 bpm after 5 minutes. Withdrawal and urge to smoke decreased and the e-cigarettes were described as satisfying. Conclusions: E-cigarettes can deliver levels of nicotine that are comparable to or higher than typical tobacco cigarettes, with similar systemic retention. Although the average maximum plasma nicotine concentration in experienced e-cigarettes users appears to be generally lower than what has been reported from tobacco cigarette use, the shape of the pharmacokinetic curve is similar, suggesting addictive potential. This article is protected by copyright. All rights reserved.
    Addiction 10/2015; DOI:10.1111/add.13183 · 4.74 Impact Factor
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    ABSTRACT: Background: The Food and Drug Administration can set standards that reduce the nicotine content of cigarettes. Methods: We conducted a double-blind, parallel, randomized clinical trial between June 2013 and July 2014 at 10 sites. Eligibility criteria included an age of 18 years or older, smoking of five or more cigarettes per day, and no current interest in quitting smoking. Participants were randomly assigned to smoke for 6 weeks either their usual brand of cigarettes or one of six types of investigational cigarettes, provided free. The investigational cigarettes had nicotine content ranging from 15.8 mg per gram of tobacco (typical of commercial brands) to 0.4 mg per gram. The primary outcome was the number of cigarettes smoked per day during week 6. Results: A total of 840 participants underwent randomization, and 780 completed the 6-week study. During week 6, the average number of cigarettes smoked per day was lower for participants randomly assigned to cigarettes containing 2.4, 1.3, or 0.4 mg of nicotine per gram of tobacco (16.5, 16.3, and 14.9 cigarettes, respectively) than for participants randomly assigned to their usual brand or to cigarettes containing 15.8 mg per gram (22.2 and 21.3 cigarettes, respectively; P<0.001). Participants assigned to cigarettes with 5.2 mg per gram smoked an average of 20.8 cigarettes per day, which did not differ significantly from the average number among those who smoked control cigarettes. Cigarettes with lower nicotine content, as compared with control cigarettes, reduced exposure to and dependence on nicotine, as well as craving during abstinence from smoking, without significantly increasing the expired carbon monoxide level or total puff volume, suggesting minimal compensation. Adverse events were generally mild and similar among groups. Conclusions: In this 6-week study, reduced-nicotine cigarettes versus standard-nicotine cigarettes reduced nicotine exposure and dependence and the number of cigarettes smoked. (Funded by the National Institute on Drug Abuse and the Food and Drug Administration Center for Tobacco Products; number, NCT01681875.).
    New England Journal of Medicine 10/2015; 373(14):1340-1349. DOI:10.1056/NEJMsa1502403 · 55.87 Impact Factor
  • Judith J Prochaska · Neal L Benowitz ·
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    ABSTRACT: The tobacco addiction treatment field is progressing through innovations in medication development, a focus on precision medicine, and application of new technologies for delivering support in real time and over time. This article reviews the evidence for combined and extended cessation pharmacotherapy and behavioral strategies including provider advice, individual counseling, group programs, the national quitline, websites and social media, and incentives. Healthcare policies are changing to offer cessation treatment to the broad population of smokers. With knowledge of the past and present, this review anticipates what is likely on the horizon in the clinical and public health effort to address tobacco addiction. Expected final online publication date for the Annual Review of Medicine Volume 67 is January 14, 2016. Please see for revised estimates.
    Annual review of medicine 09/2015; 67(1). DOI:10.1146/annurev-med-111314-033712 · 12.93 Impact Factor
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    ABSTRACT: A broadly mandated reduction of the nicotine content (RNC) of cigarettes has been proposed in the United States to reduce the addictiveness of cigarettes, to prevent new smokers from becoming addicted and to facilitate quitting in established smokers. The primary aim of this study was to determine whether following 7 months of smoking very low nicotine content cigarettes (VLNC), and then returning to their own cigarettes, smokers would demonstrate persistently reduced nicotine intake compared with baseline or quit smoking. In a community-based clinic 135 smokers not interested in quitting were randomized to one of two groups. A research group smoked their usual brand of cigarettes, followed by five types of research cigarettes with progressively lower nicotine content, each for 1 month, followed by 6 months at the lowest nicotine level (0.5 mg/cigarette) (53 subjects) and then 12 months with no intervention (30 subjects completed). A control group smoked their usual brand for the same period of time (50 subjects at 6 months, 38 completed). Smoking behavior, biomarkers of nicotine intake and smoke toxicant exposure were measured. After 7 months smoking VLNC, nicotine intake remained below baseline (plasma cotinine 149 versus 250 ng/ml, P<0.005) with no significant change in cigarettes per day or expired carbon monoxide (CO). During the 12-month follow-up, cotinine levels in RNC smokers rose to baseline levels and to those of control smokers. Quit rates among RNC smokers were very low [7.5 versus 2% in controls, not significant). In smokers not interested in quitting, reducing the nicotine content in cigarettes over 12 months does not appear to result in extinction of nicotine dependence, assessed by persistently reduced nicotine intake or quitting smoking over the subsequent 12 months. © 2015 Society for the Study of Addiction.
    Addiction 07/2015; 110(10). DOI:10.1111/add.12978 · 4.74 Impact Factor
  • Judith J Prochaska · Neal L Benowitz ·
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    ABSTRACT: Smoking remains the leading cause of preventable morbidity and mortality. Our review highlights research from 2013 to 2015 on the treatment of cigarette smoking, with a focus on heart patients and cardiovascular outcomes. Seeking to maximize the reach and effectiveness of existing cessation medications, current tobacco control research has demonstrated the safety and efficacy of combination treatment, extended use, reduce-to-quit strategies, and personalized approaches to treatment matching. Further, cytisine has gained interest as a lower-cost strategy for addressing the global tobacco epidemic. On the harm reduction front, snus and electronic nicotine delivery systems are being widely distributed and promoted with major gaps in knowledge of the safety of long-term and dual use. Quitlines, comparable in outcome to in-person treatment, make cessation counseling available on a national scale, though use rates remain relatively low. Employee reward programs are gaining attention given the high costs of tobacco use to employers; sustaining quit rates postpayment, however, has proven challenging. Evidence-based cessation treatments exist. Broader dissemination, adoption, and implementation are key to addressing the tobacco epidemic. The cardiology team has a professional obligation to advance tobacco control efforts and can play an important role in achieving a smoke-free future.
    Current opinion in cardiology 07/2015; 30(5). DOI:10.1097/HCO.0000000000000204 · 2.70 Impact Factor
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    ABSTRACT: The Nicotine Metabolite Ratio (NMR, ratio of trans-3'-hydroxycotinine and cotinine), has previously been associated with CYP2A6 activity, response to smoking cessation treatments, and cigarette consumption. We searched for drug metabolizing enzyme and transporter (DMET) gene variation associated with the NMR and prospective abstinence in 2,946 participants of laboratory studies of nicotine metabolism and of clinical trials of smoking cessation therapies. Stage I was a meta-analysis of the association of 507 common single nucleotide polymorphisms (SNPs) at 173 DMET genes with the NMR in 449 participants of two laboratory studies. Nominally significant associations were identified in ten genes after adjustment for intragenic SNPs; CYP2A6 and two CYP2A6 SNPs attained experiment-wide significance adjusted for correlated SNPs (CYP2A6 PACT=4.1E-7, rs4803381 PACT=4.5E-5, rs1137115, PACT=1.2E-3). Stage II was mega-regression analyses of 10 DMET SNPs with pretreatment NMR and prospective abstinence in up to 2,497 participants from eight trials. rs4803381 and rs1137115 SNPs were associated with pretreatment NMR at genome-wide significance. In post-hoc analyses of CYP2A6 SNPs, we observed nominally significant association with: abstinence in one pharmacotherapy arm; cigarette consumption among all trial participants; and lung cancer in four case:control studies. CYP2A6 minor alleles were associated with reduced NMR, CPD, and lung cancer risk. We confirmed the major role that CYP2A6 plays in nicotine metabolism, and made novel findings with respect to genome-wide significance and associations with CPD, abstinence and lung cancer risk. Additional multivariate analyses with patient variables and genetic modeling will improve prediction of nicotine metabolism, disease risk and smoking cessation treatment prognosis.
    PLoS ONE 07/2015; 10(7):e0126113. DOI:10.1371/journal.pone.0126113 · 3.23 Impact Factor
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    ABSTRACT: The highly genetically variable enzyme CYP2A6 metabolizes nicotine to cotinine (COT) and COT to trans-3'-hydroxycotinine (3HC). The nicotine metabolite ratio (NMR, 3HC/COT) is commonly used as a biomarker of CYP2A6 enzymatic activity, rate of nicotine metabolism, and total nicotine clearance; NMR is associated with numerous smoking phenotypes, including smoking cessation. Our objective was to investigate the impact of different measurement methods, at different sites, on plasma and urinary NMR measures from ad libitum smokers. Plasma (n=35) and urine (n=35) samples were sent to eight different laboratories, which employed similar and different methods of COT and 3HC measurements to derive the NMR. We used Bland-Altman analysis to assess agreement, and Pearson correlations to evaluate associations, between NMR measured by different methods. Measures of plasma NMR were in strong agreement between methods according to Bland-Altman analysis (ratios 0.82-1.16) and were highly correlated (all Pearson r>0.96, P<0.0001). Measures of urinary NMR were in relatively weaker agreement (ratios 0.62-1.71) and less strongly correlated (Pearson r values of 0.66-0.98, P<0.0001) between different methods. Plasma and urinary COT and 3HC concentrations, while weaker than NMR, also showed good agreement in plasma, which was better than in urine, as was observed for NMR. Plasma is a very reliable biological source for the determination of NMR, robust to differences in these analytical protocols or assessment site. Together this indicates a reduced need for differential interpretation of plasma NMR results based on the approach used, allowing for direct comparison of different studies. Copyright © 2015, American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 05/2015; 24(8). DOI:10.1158/1055-9965.EPI-14-1381 · 4.13 Impact Factor
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    ABSTRACT: CHRNA5-A3-B4 variants, rs16969968, rs588765 and rs578776, are consistently associated with tobacco consumption among smokers, but the association with smoking cessation is less consistent. Among the studies that reported significant associations with cessation, the effects were observed in smokers treated with placebo treatment in some studies and conversely in those receiving active pharmacological therapy (bupropion and nicotine replacement therapies) in others. Thus, it remains unclear whether CHRNA5-A3-B4 is a useful marker for optimizing smoking cessation. Using data from 654 Caucasian smokers treated with placebo, nicotine patch or varenicline, we investigated whether CHRNA5-A3-B4 variants were associated with smoking cessation outcomes, and whether there were significant genotype-by-treatment or haplotype-by-treatment interactions. We observed no significant associations between CHRNA5-A3-B4 variants and smoking cessation, despite replicating previous associations with baseline tobacco consumption. At end of treatment the effect size on smoking cessation in the placebo, patch and varenicline groups for rs16969968 [GG vs. GA+AA] was OR = 0.66 (P = 0.23), OR = 1.01 (P = 0.99), and OR = 1.30 (P = 0.36) respectively, of rs588765 [CC vs. CT+TT] was OR = 0.96 (P = 0.90), OR = 0.84 (P = 0.58), and OR = 0.74 (P = 0.29) respectively, and for rs578776 [GG vs. GA+AA] on smoking cessation was OR = 1.02 (P = 0.95), OR = 0.75 (P = 0.35), and OR = 1.20 (P = 0.51) respectively. Furthermore, we observed no associations with cessation using the CHRNA5-A3-B4 haplotype (constructed using rs16969968 and rs588765), nor did we observe any significant genotype-by-treatment interactions, with or without adjusting for the rate of nicotine metabolism (all P>0.05). We also observed no significant genetic associations with 6 month or 12 month smoking abstinence. In conclusion, we found no association between CHRNA5-A3-B4 variants and smoking cessation rates in this clinical trial; however, as expected, significant associations with baseline tobacco consumption were replicated. Our data suggest that CHRNA5-A3-B4 gene variants do not exhibit a robust association with smoking cessation and are unlikely to be useful for clinically optimizing smoking cessation pharmacotherapy for Caucasian smokers.
    PLoS ONE 05/2015; 10(5):e0128109. DOI:10.1371/journal.pone.0128109 · 3.23 Impact Factor
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    ABSTRACT: The association between cigarette smoke exposure and the acute respiratory distress syndrome in patients with the most common acute respiratory distress syndrome risk factors of sepsis, pneumonia, and aspiration has not been well studied. The goal of this study was to test the association between biomarker-confirmed cigarette smoking and acute respiratory distress syndrome in a diverse cohort. Prospective cohort. Tertiary care center. Four hundred twenty-six critically ill patients with acute respiratory distress syndrome risk factors (excluding trauma and transfusion) INTERVENTIONS:: None. We obtained smoking histories and measured urine 4-(methylnitrosamino)-1-(3-pyridyl)-1--butanol (a biomarker of cigarette smoke exposure) on urine samples obtained at the time of study enrollment. The association between cigarette smoke exposure and acute respiratory distress syndrome differed based on acute respiratory distress syndrome risk factor (p < 0.02 for interaction). In patients with nonpulmonary sepsis as the primary acute respiratory distress syndrome risk factor (n = 212), 39% of those with acute respiratory distress syndrome were current smokers by history compared with 22% of those without acute respiratory distress syndrome (odds ratio, 2.28; 95% CI, 1.24-4.19; p = 0.008). Likewise, cigarette smoke exposure as measured by urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol was significantly associated with acute respiratory distress syndrome in this group. The increased risk of acute respiratory distress syndrome in nonpulmonary sepsis was restricted to patients with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels consistent with active smoking and was robust to adjustment for other acute respiratory distress syndrome predictors. Cigarette smoke exposure as measured by history or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol was not associated with acute respiratory distress syndrome in patients with other risk factors (e.g., pneumonia and aspiration). Cigarette smoking measured both by history and biomarker is associated with an increased risk of acute respiratory distress syndrome in patients with nonpulmonary sepsis. This finding has important implications for tobacco product regulation and for understanding the pathogenesis of acute respiratory distress syndrome.
    Critical care medicine 05/2015; 43(9). DOI:10.1097/CCM.0000000000001089 · 6.31 Impact Factor
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    ABSTRACT: The nicotine metabolite ratio (NMR) of 3'-hydroxycotinine to cotinine is a noninvasive marker of the rate of nicotine metabolism. Fast metabolism (i.e., a high NMR) is associated with lower cigarette smoking abstinence rates using transdermal nicotine replacement. We evaluated whether the NMR can be used to predict self-reported nicotine lozenge use and tobacco abstinence among smokeless tobacco users treated for tobacco dependence. This was a secondary analysis of data from one arm of a large trial. Participants received quitting support materials and 4-mg nicotine lozenges by mail plus three coaching phone calls. Saliva kits were mailed for collection of saliva samples, which were analyzed for cotinine and 3'-hydroxycotinine. Self-reported tobacco and lozenge use were assessed at 3 months. Analyses were performed using Spearman rank correlation and logistic regression. Of the 160 saliva collection kits mailed, 152 were returned. The NMR was not significantly correlated with the baseline amount of smokeless tobacco used, the number of years of tobacco use, or the level of tobacco dependence as measured by the Severson Scale of Tobacco Dependence. The NMR was positively correlated with lozenge use (r = 0.21, p = .015), but it did not predict self-reported 7-day point prevalence abstinence at 3 months. Fast metabolizers may need to self-administer more nicotine replacement in the form of nicotine lozenges to achieve the same clinical response achieved by slower metabolizers using fewer lozenges. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail:
    Nicotine & Tobacco Research 05/2015; DOI:10.1093/ntr/ntv102 · 3.30 Impact Factor
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    ABSTRACT: Background: Cardiovascular disease is the leading cause of death, and smoking cessation is a key component of secondary cardiovascular disease risk prevention efforts. Objectives: To examine the relationships between demographic, clinical and health factors, history and patterns of smoking, nicotine dependence, withdrawal symptoms, and willingness (i.e., readiness) to quit smoking after hospital discharge among adult Jordanian men who were cigarette smokers and were admitted to the hospital with a cardiovascular disease diagnosis. Methods: This cross-sectional study recruited 118 adult men smokers from three hospitals in Jordan during 2011. Data were collected using structured interviews and medical record abstraction. Results: The mean age of smokers was 50.7 (±6.7) years and they smoked at least one cigarette per day for an average of 28.8 years (±7.0). Currently they smoke an average of 28.9 (±8.0) cigarettes a day. About a quarter (24.6%, n = 29) had previously made a quit attempt that lasted at least 24 hours. Smokers were considered highly nicotine dependent if they had scores of > 6 (out of 10) on the Fagerström Test for Nicotine Dependence scale. The average nicotine dependence score was significantly higher in the high versus low nicotine dependence group (6.9 vs. 4.1). The number of cigarettes smoked daily was significantly higher in the high compared to the low nicotine dependence group (30.7 cigarettes vs. 23.4). Logistic regression showed smokers who had someone available to encourage quitting smoking “at least sometimes” were more likely to quit smoking after hospital discharge, and smokers who had sufficient personal income to support self were less likely to quit smoking after hospital discharge, while controlling for all other variables. Conclusions: The very high nicotine dependence of these men indicates that there is an urgent need for education, counseling and behavioral interventions, and pharmacological therapies, to achieve successful smoking cessation. Study findings lay the basis for development of appropriate smoking cessation programs in Jordan.
    05/2015; 5(5):21-34. DOI:10.5430/jnep.v5n5p21
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    ABSTRACT: Smokeless tobacco products, such as moist snuff or chewing tobacco, contain many of the same carcinogens as tobacco smoke; however the impact on children of indirect exposure to tobacco constituents via parental smokeless tobacco use is unknown. As part of the California Childhood Leukemia Study, dust samples were collected from 6 homes occupied by smokeless tobacco users, 6 homes occupied by active smokers, and 20 tobacco-free homes. To assess children's potential for exposure to tobacco constituents, vacuum-dust concentrations of five tobacco-specific nitrosamines, including N'-nitrosonornicotine [NNN] and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK], as well as six tobacco alkaloids, including nicotine and myosmine were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We used generalized estimating equations derived from a multivariable marginal model to compare levels of tobacco constituents between groups, after adjusting for a history of parental smoking, income, home construction date, and mother's age and race/ethnicity. The ratio of myosmine:nicotine was used as a novel indicator of the source of tobacco contamination, distinguishing between smokeless tobacco products and tobacco smoke. Median dust concentrations of NNN and NNK were significantly greater in homes with smokeless tobacco users compared to tobacco-free homes. In multivariable models, concentrations of NNN and NNK were 4.8-fold and 6.9-fold higher in homes with smokeless tobacco users compared to tobacco-free homes. Median myosmine:nicotine ratios were lower in homes with smokeless tobacco users (1.8%) compared to homes of active smokers (7.7%), confirming that cigarette smoke was not the predominant source of tobacco constituents in homes with smokeless tobacco users. Children living with smokeless tobacco users may be exposed to carcinogenic tobacco-specific nitrosamines via contact with contaminated dust and household surfaces.
    Chemical Research in Toxicology 03/2015; 28(5). DOI:10.1021/acs.chemrestox.5b00040 · 3.53 Impact Factor
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    ABSTRACT: A number of candidate gene and genome-wide association studies have identified significant associations between single nucleotide polymorphisms, particularly in FTO and MC4R, and body weight. However, the association between copy number variation and body weight is less understood. Anabolic androgenic steroids, such as testosterone, can regulate body weight. In humans, UDP-glucuronosyltransferase 2B17 (UGT2B17) metabolizes testosterone to a metabolite, which is readily excreted in urine. We investigate the association between genetic and phenotypic variation in UGT2B17 and body weight. UGT2B17 deletion was genotyped and in-vivo UGT2B17 enzymatic activity (as measured by the 3-hydroxycotinine glucuronide to free 3-hydroxycotinine ratio) was measured in 400 Alaska Native individuals and 540 African Americans. In Alaska Native people, UGT2B17 deletion was strongly associated with lower BMI in male individuals (P<0.001), but not in female individuals, consistent with testosterone being a male dominant steroid. The sex-specific association between UGT2B17 deletion and lower BMI was also observed in African Americans (P=0.01 in male individuals). In both populations, UGT2B17 deletion was significantly associated with lower measured in-vivo UGT2B17 activity. In male individuals, lower in-vivo UGT2B17 activity was associated with lower BMI, as observed in the sex-specific genotypic association. These data suggest that UGT2B17 deletion leads to reduced UGT2B17 activity, and lower BMI in male individuals. This is consistent with the hypothesis that reduced UGT2B17-mediated testosterone excretion results in higher testosterone levels. Future studies could confirm this hypothesis by directly measuring serum testosterone levels.
    Pharmacogenetics and Genomics 03/2015; 25(5). DOI:10.1097/FPC.0000000000000135 · 3.48 Impact Factor
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    ABSTRACT: In recent years, new products have entered the marketplace that complicate decisions about tobacco control policies and prevention in the workplace. These products, called electronic cigarettes (e-cigarettes) or electronic nicotine delivery systems, most often deliver nicotine as an aerosol for inhalation, without combustion of tobacco. This new mode of nicotine delivery raises several questions about the safety of the product for the user, the effects of secondhand exposure, how the public use of these products should be handled within tobacco-free and smoke-free air policies, and how their use affects tobacco cessation programs, wellness incentives, and other initiatives to prevent and control tobacco use. In this article, we provide a background on e-cigarettes and then outline key policy recommendations for employers on how the use of these new devices should be managed within worksite tobacco prevention programs and control policies.
    Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine 03/2015; 57(3):334-43. DOI:10.1097/JOM.0000000000000420 · 1.63 Impact Factor
  • Rachel Grana · Neal Benowitz · Stanton Glantz ·

    Circulation 02/2015; 131(6):e342-e342. DOI:10.1161/CIRCULATIONAHA.114.012887 · 14.43 Impact Factor
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    ABSTRACT: Substantial variability exists in therapeutic response and adverse effects with pharmacotherapies for tobacco dependence. Biomarkers to optimise treatment choice for individual smokers might improve treatment outcomes. We tested whether a genetically informed biomarker of nicotine clearance, the nicotine metabolite ratio (NMR; 3'-hydroxycotinine:cotinine), predicts response to nicotine patch or varenicline for smoking cessation. We undertook NMR-stratified multicentre, randomised, placebo-controlled clinical trial from Nov 16, 2010, to Sept 12, 2014, at four sites. Smokers seeking treatment were randomly assigned by baseline NMR status and study site, in blocks of 12 patients (1:1:1 ratio), to 11 weeks of placebo (placebo pill plus placebo patch), nicotine patch (active patch plus placebo pill), or varenicline (active pill plus placebo patch), plus behavioural counselling. Participants and investigators were masked to group allocation and NMR status. An intention-to-treat analysis was done. Participants were followed up for 12 months after the target quit date. The primary endpoint was biochemically verified 7 day point prevalence abstinence at the end of treatment to estimate the pharmacological effect of treatment by NMR. The trial is registered at, number NCT01314001. 1246 participants (662 slow metabolisers of nicotine, 584 normal metabolisers of nicotine) were enrolled and randomly assigned to the three interventions (408 placebo, 418 nicotine patch, 420 varenicline). At end of treatment, varenicline was more efficacious than nicotine patch in normal metabolisers (OR 2·17, 95% CI 1·38-3·42; p=0·001), but not in slow metabolisers (OR 1·13, 0·74-1·71; p=0·56). In the longitudinal model including all timepoints, the NMR-by-treatment interaction was significant (ratio of odds ratios [ORR] 1·96, 95% CI 1·11-3·46; p=0·02). An NMR-by-treatment interaction showed that slow (vs normal) metabolisers reported greater overall side-effect severity with varenicline versus placebo (β=-1·06, 95% CI -2·08 to -0·03; p=0·044). Treating normal metabolisers with varenicline and slow metabolisers with nicotine patch could optimise quit rates while minimising side-effects. National Institutes of Health, Canadian Institutes of Health Research, Abramson Cancer Center, Centre for Addiction and Mental Health Foundation, and Pennsylvania Department of Health. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Respiratory Medicine 01/2015; 3(2). DOI:10.1016/S2213-2600(14)70294-2 · 9.63 Impact Factor
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    ABSTRACT: The Food and Drug Administration (FDA) has the authority to regulate tobacco product constituents, including nicotine, to promote public health. Reducing the nicotine content in cigarettes may lead to lower levels of addiction. Smokers however may compensate by smoking more cigarettes and/or smoking more intensely. The objective of this study was to test whether individual differences in the level of nicotine dependence (as measured by the Fagerstrom Test of Cigarette Dependence, FTCD) and/or the rate of nicotine metabolism influence smoking behavior and exposure to tobacco toxicants when smokers are switched to reduced nicotine content cigarettes (RNC). Data from 51 participants from a previously published clinical trial of RNC were analyzed. Nicotine content of cigarettes was progressively reduced over six months and measures of smoking behavior, as well as nicotine metabolites and tobacco smoke toxicant exposure, CYP2A6 and nicotinic CHRNA5-A3-B4 (rs1051730) genotype were measured. Higher baseline FTCD predicted smoking more cigarettes per day (CPD), higher cotinine and smoke toxicant levels while smoking RNC throughout the study, with no interaction by RNC level. Time to first cigarette (TFC) was associated with differences in compensation. TFC within 10 min was associated with a greater increase in CPD compared to TFC greater than 10 min. Neither rate of nicotine metabolism, nor CYP2A6 or nicotinic receptor genotype, had an effect on the outcome variables of interest. FTCD is associated with overall exposure to nicotine and other constituents of tobacco smoke, while a short TFC is associated with an increased compensatory response after switching to RNC. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail:
    Nicotine & Tobacco Research 01/2015; 17(9). DOI:10.1093/ntr/ntu337 · 3.30 Impact Factor
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    ABSTRACT: Differences in carcinogen exposure from different cigarette products could contribute to differences in smoking-associated cancer incidence among Chinese compared with US smokers. Urine concentrations of metabolites of nicotine, the tobacco-specific nitrosamine (TSNA) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and polycyclic aromatic hydrocarbon metabolites (PAHs) were compared in 238 Chinese and 203 US daily smokers. Comparing Chinese versus US smokers, daily nicotine intake and nicotine intake per cigarette smoked were found to be similar. When normalised for cigarettes per day, urine NNAL excretion was fourfold higher in US smokers, while the excretion of urine metabolites of the PAHs fluorene, phenanthrene and pyrene metabolites was 50% to fourfold higher in Chinese smokers (all, p<0.0001). Similar results were seen when NNAL and PAHs excretion was normalised for daily nicotine intake. Patterns of carcinogen exposure differ, with lower exposure to TSNA and higher exposure to PAHs in Chinese compared with US smokers. These results most likely reflect country differences in cigarette tobacco blends and manufacturing processes, as well as different environmental exposures. NCT00264342. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
    Tobacco Control 12/2014; DOI:10.1136/tobaccocontrol-2014-051945 · 5.93 Impact Factor
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    ABSTRACT: Reducing the addictiveness of cigarettes by reducing their nicotine content can potentially have a profound impact on public health. Two different approaches to nicotine reduction have been proposed: gradual and immediate. To determine if either of these approaches results in significant compensatory smoking behavior, which might lead to safety concerns, we performed a secondary analysis of data from studies that have utilized these two approaches. The number of cigarettes smoked per day, carbon monoxide exposure, and cotinine levels in plasma or urine were assessed while participants smoked reduced nicotine content cigarettes and compared to when they smoked their usual brand cigarettes. The results showed that in general, these two approaches led to minimal compensatory smoking and reduced levels of cotinine over the course of the experimental period, suggesting that neither of these approaches poses a major safety concern. Copyright © 2014, American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 12/2014; 24(2). DOI:10.1158/1055-9965.EPI-14-0739 · 4.13 Impact Factor
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    Neal L Benowitz · Natalie Nardone · Dorothy K Hatsukami · Eric C Donny ·
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    ABSTRACT: Background: The reduction of the nicotine content of cigarettes to non-addicting levels is a potential federal regulatory intervention to reduce the prevalence of cigarette smoking and related disease. Many clinical trials on the effects and safety of nicotine reduction are ongoing. An important methodological concern is non-compliance with reduced nicotine content cigarettes in the context of freely available conventional cigarettes. We propose two approaches using biomarkers to estimate non-compliance in smokers of very low nicotine content (VLNC) cigarettes in a clinical trial. Methods: Data from 50 subjects in a study of gradual nicotine reduction were analyzed. Using plasma cotinine concentrations measured at baseline and while smoking VLNC cigarettes, we compared within-subject ratios of plasma cotinine comparing usual brand to VLNC in relation to nicotine content of these cigarettes. In another approach we used nicotine pharmacokinetic data to estimate absolute plasma cotinine/cigarettes per day (CPD) threshold values for compliance based on the nicotine content of VLNC. Results: The two approaches showed concordance indicating at least 60% non-compliance with smoking VLNC. In a sensitivity analysis assuming extreme compensation and extreme values for nicotine metabolic parameters, non-compliance was still at least 40%, much higher than self-reported non-compliance. Conclusion: Biomarker analysis demonstrates a high degree of non-compliance with smoking VLNC cigarettes, indicating that smokers are supplementing these with conventional cigarettes. Impact: We propose a practical approach to assessing compliance with smoking VLNC in clinical trials of nicotine reduction. Copyright © 2014, American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 11/2014; 24(2). DOI:10.1158/1055-9965.EPI-14-1040 · 4.13 Impact Factor

Publication Stats

30k Citations
4,602.75 Total Impact Points


  • 1979-2015
    • San Francisco VA Medical Center
      San Francisco, California, United States
    • Clinical pharmacology of Miami
      Miami, Florida, United States
  • 1976-2015
    • University of California, San Francisco
      • • Department of Bioengineering and Therapeutic Sciences
      • • Division of Clinical Pharmacology & Experimental Therapeutics
      • • Department of Medicine
      • • Department of Clinical Pharmacy
      • • Department of Physiological Nursing
      • • Department of Oral and Maxillofacial Surgery
      • • Division of Hospital Medicine
      • • Department of Psychiatry
      San Francisco, California, United States
  • 1999-2014
    • Stanford University
      • • Department of Medicine
      • • Stanford Prevention Research Center
      Palo Alto, California, United States
  • 2012
    • Emory University
      • Department of Behavioral Sciences and Health Education
      Atlanta, Georgia, United States
  • 2010
    • University of Oulu
      • Department of Internal Medicine
      Uleoborg, Oulu, Finland
    • Robert Wood Johnson University Hospital
      New Brunswick, New Jersey, United States
  • 2006-2010
    • University of Toronto
      • Department of Pharmacology and Toxicology
      Toronto, Ontario, Canada
    • Environmental Science & Research
      Окленд, Auckland, New Zealand
    • IWK Health Centre
      Halifax, Nova Scotia, Canada
  • 2009
    • Jazz Pharmaceuticals plc
      Dublin, Leinster, Ireland
    • Cardiovascular Research Foundation
      New York, New York, United States
  • 2007-2009
    • San Diego State University
      • • Graduate School of Public Health
      • • Department of Psychology
      San Diego, CA, United States
    • Queen's University
      Kingston, Ontario, Canada
  • 2008
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 1995-2008
    • CSU Mentor
      Long Beach, California, United States
  • 1989-2006
    • Johns Hopkins University
      • • Department of Biostatistics
      • • Department of Medicine
      Baltimore, MD, United States
  • 2005
    • University of Michigan
      Ann Arbor, Michigan, United States
  • 2004
    • University of Pennsylvania
      • Transdisciplinary Tobacco Use Research Center - TTURC
      Filadelfia, Pennsylvania, United States
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem, Israel
  • 2000
    • Shaare Zedek Medical Center
      • Department of Medicine
      Yerushalayim, Jerusalem, Israel
    • Skidmore College
      Saratoga Springs, New York, United States
  • 1998-1999
    • University of San Francisco
      San Francisco, California, United States
  • 1985-1998
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
  • 1997
    • Baylor College of Medicine
      • Section of Cardiology
      Houston, Texas, United States
  • 1996
    • Monash University (Australia)
      • Department of Epidemiology and Preventive Medicine
      Melbourne, Victoria, Australia
  • 1993
    • San Francisco Bay Area for Cognitive Therapy
      San Francisco, California, United States
  • 1992
    • Eli Lilly
      Indianapolis, Indiana, United States
  • 1990-1992
    • University of Pittsburgh
      • Psychology
      Pittsburgh, Pennsylvania, United States
    • National Institute on Drug Abuse
      Роквилл, Maryland, United States
  • 1991
    • National Cancer Institute (USA)
      • Occupational and Environmental Epidemiology
      Maryland, United States
  • 1984
    • Case Western Reserve University
      Cleveland, Ohio, United States
  • 1983
    • Hennepin County Medical Center
      Minneapolis, Minnesota, United States