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CORK Bibliography: Biological Markers for Substance Use

67 citations. January 2010 to present

Prepared: March 2012

Achur RN; Freeman WM; Vrana KE. Circulating cytokines as biomarkers of alcohol abuse and alcoholism. (review). Journal of Neuroimmune Pharmacology 5(1): 83-91, 2010. (72 refs.)

There are currently no consistent objective biochemical markers of alcohol abuse and alcoholism. Development of reliable diagnostic biomarkers that permit accurate assessment of alcohol intake and patterns of drinking is of prime importance to treatment and research fields. Diagnostic biomarker development in other diseases has demonstrated the utility of both open, systems biology, screening for biomarkers and more rational focused efforts on specific biomolecules or families of biomolecules. Long-term alcohol consumption leads to altered inflammatory cell and adaptive immune responses with associated pathologies and increased incidence of infections. This has led researchers to focus attention on identifying cytokine biomarkers in models of alcohol abuse. Alcohol is known to alter cytokine levels in plasma and a variety of tissues including lung, liver, and very importantly brain. A number of cytokine biomarker candidates have been identified, including: tumor necrosis factor-alpha, interleukin (IL)-1-alpha, IL-1-beta, IL-6, IL-8, IL-12, and monocyte chemoattractant protein-1. This is an emerging and potentially exciting avenue of research in that circulating cytokines may contribute to diagnostic biomarker panels, and a combination of multiple biomarkers may significantly increase the sensitivity and specificity of the biochemical tests aiding reliable and accurate detection of excessive alcohol intake.

Alonso M; Castellanos M; Sanchez JM. Evaluation of potential breath biomarkers for active smoking: Assessment of smoking habits. Analytical and Bioanalytical Chemistry 396(8): 2987-2995, 2010. (31 refs.)

Different compounds have been reported as biomarkers of a smoking habit, but, to date, there is no appropriate biomarker for tobacco-related exposure because the proposed chemicals seem to be nonspecific or they are only appropriate for short-term exposure. Moreover, conventional sampling methodologies require an invasive method because blood or urine samples are required. The use of a microtrap system coupled to gas chromatography-mass spectrometry analysis has been found to be very effective for the noninvasive analysis of volatile organic compounds in breath samples. The levels of benzene, 2, 5-dimethylfuran, toluene, o-xylene, and m- p-xylene have been analyzed in breath samples obtained from 204 volunteers (100 smokers, 104 nonsmokers; 147 females, 57 males; ages 16 to 53 years). 2,5-Dimethylfuran was always below the limit of detection (0.005 ppbv) in the nonsmoker population and always detected in smokers independently of the smoking habits. Benzene was only an effective biomarker for medium and heavy smokers, and its level was affected by smoking habits. Regarding the levels of xylenes and toluene, they were only different in heavy smokers and after short-term exposure. The results obtained suggest that 2,5-dimethylfuran is a specific breath biomarker of smoking status independently of the smoking habits (e.g., short-and long-term exposure, light and heavy consumption), and so this compound might be useful as a biomarker of smoking exposure.

Anderson NE; Baldridge RM; Stanford MS. P3a amplitude predicts successful treatment program completion in substance-dependent individuals. Substance Use & Misuse 46(5): 669-677, 2011. (48 refs.)

This study examined P3a amplitude as a direct predictor of treatment success for substance dependence. Participants were 35 adults (27 men, 8 women) undergoing treatment for substance dependence at an urban residential treatment facility between October 2005 and July 2007. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria were used to confirm substance dependence. P3a amplitude was significantly smaller for those who dropped out of treatment. Discriminant function analysis confirmed that P3a amplitude was a robust predictor of treatment completion, more sensitive than other measures including substance abuse severity. Implications for the interpretation of P3a amplitude as an index of executive function are discussed.

Andrew C; Fein g. Event-related oscillations versus event-related potentials in a p300 task as biomarkers for alcoholism. Alcoholism: Clinical and Experimental Research 34(4): 669-680, 2010. (46 refs.)

Objective: It has been proposed that event-related oscillation (ERO) measures of EEG activity recorded in P300 tasks provide more powerful biomarkers of alcoholism than event-related potential (ERP) measures. This study examines this question in a group of long-term abstinent alcoholics (LTAAs). Methods: EEGs were recorded on 48 LTAAs and 48 age and gender-matched nonalcoholic controls (NACs) during the performance of a 3-condition visual target detection task. The event-related data were analyzed to extract ERP amplitude measures and total and evoked ERO power measures. Data were analyzed using multivariate analysis of covariance to determine the contributions of ERO versus ERP measures to discriminate between the LTAA versus NAC groups. Results: The LTAA group showed significantly lower evoked delta ERO power and total delta and theta ERO power compared to the control group. The evoked and total ERO power measures provide an alternative (but not more powerful) representation of the group difference than does P3b amplitude. There was a weak suggestion that nonphase-locked theta ERO power (which contributes to total ERO power) might provide independent discriminatory information. Conclusions: Reduced evoked ERO power in the response to target stimuli provided an alternative and comparable representation of the reduced P3b amplitude in LTAA. This is not surprising as the evoked ERO power measures are derived from time-frequency representations of the ERP waveform. Induced theta oscillations might provide independent discriminatory information beyond ERP amplitude measures, but separate analysis of the event-related nonphase-locked activity is required to investigate this further.

Andrew C; Fein G. Induced theta oscillations as biomarkers for alcoholism. Clinical Neurophysiology 121(3): 350-358, 2010. (29 refs.)

Objective: Studies have suggested that non-phase-locked event-related oscillations (ERO) in target stimulus processing might provide biomarkers of alcoholism. This study investigates the discriminatory power of non-phase-locked oscillations in a group of long-term abstinent alcoholics (LTAAs) and nonalcoholic controls (NACs). Methods: EEGs were recorded from 48 LTAAs and 48 age and gender comparable NACs during rest with eyes open (EO) and during the performance of a three-condition visual target detection task. The data were analyzed to extract resting power, ERP amplitude and non-phase-locked ERO power measures. Data were analyzed using MANCOVA to determine the discriminatory power of induced theta ERO vs. resting theta power vs. P300 ERP measures in differentiating the LTAA and NAC groups. Results: Both groups showed significantly more theta power in the pre-stimulus reference period of the task vs. the resting EO condition. The resting theta power did not discriminate the groups, while the LTAAs showed significantly less pre-stimulus theta power vs. the NACs. The LTAAs showed a significantly larger theta event-related synchronization (ERS) to the target stimulus vs. the NACs, even after accounting for pre-stimulus theta power levels. ERS to non-target stimuli showed smaller induced oscillations vs. target stimuli with no group differences. Alcohol use variables, a family history of alcohol problems, and the duration of alcohol abstinence were not associated with any theta power measures. Conclusions: While reference theta power in the task and induced theta oscillations to target stimuli both discriminate LTAAs and NACs, induced theta oscillations better discriminate the groups. Induced theta power measures are also more powerful and independent group discriminators than the P3b amplitude. Significance: Induced frontal theta oscillations promise to provide biomarkers of alcoholism that complement the well-established P300 ERP discriminators.

Babizhayev MA; Savel'yeva EL; Moskvina SN; Yegorov YE. Telomere length is a biomarker of cumulative oxidative stress, biologic age, and an independent predictor of survival and therapeutic treatment requirement associated with smoking behavior. American Journal of Therapeutics 18(6): E209-E226, 2011. (148 refs.)

Globally, tobacco use is associated with 5 million deaths per annum and is regarded as one of the leading causes of premature death. Major chronic disorders associated with smoking include cardiovascular diseases, several types of cancer, and chronic obstructive pulmonary disease (lung problems). Cigarette smoking (CS) generates a cumulative oxidative stress, which may contribute to the pathogenesis of chronic diseases. Mainstream and side stream gas-phase smoke each have about the same concentration of reactive free radical species, about 1 x 10(16) radicals per cigarette (or 5 x 10(14) per puff). This effect is critical in understanding the biologic effects of smoke. Several lines of evidence suggest that cigarette smoke constituents can directly activate vascular reactive oxygen species production. In this work we present multiple evidence that CS provide the important risk factors in many age-related diseases, and is associated with increased cumulative and systemic oxidative stress and inflammation. The cited processes are marked by increased white blood cell (leucocytes, WBCs) turnover. The data suggest an alteration of the circulating WBCs by CS, resulting in increased adherence to endothelial cells. Telomeres are complex DNA-protein structures located at the end of eukaryotic chromosomes. Telomere length shortens with biologic age in all replicating somatic cells. It has been shown that tobacco smoking enhances telomere shortening in circulating human WBCs. Telomere attrition (expressed in WBCs) can serve as a biomarker of the cumulative oxidative stress and inflammation induced by smoking and, consequently, show the pace of biologic aging. We originally propose that patented specific oral formulations of nonhydrolized carnosine and carcinine provide a powerful tool for targeted therapeutic inhibition of cumulative oxidative stress and inflammation and protection of telomere attrition associated with smoking. The longitudinal studies of the clinical population groups described in this study including elderly support the hypothesis that telomere length is a predictor of survival and therapeutic treatment requirement associated with smoking behavior.

Bean P; Harasymiw J. The reproducibility of the early detection of alcohol consumption test using split samples analyzed in different laboratories. Alcohol and Alcoholism 46(6): 694-701, 2011

This study analyzes the reproducibility of the Early Detection of Alcohol Consumption (EDAC) test by sending blood samples obtained from nine volunteers to four different laboratories. It also describes the reproducibility of the EDAC over time by analyzing the results of testing one subject whose blood sample was sent to seven different laboratories over a 10-year period. The EDAC is a method of interpreting routine laboratory profiles to identify either binge drinking or heavy drinking; the components of the routine panel were chosen based on a best fit predictions model published previously. Overall, the results of the cross-sectional analysis showed that the coefficients of variations (CVs) of the routine tests in the panel were mostly below 16%. Only three analytes (total bilirubin, aspartate aminotransferase and monocytes) showed CVs between 20 and 38%. The differences in the EDAC predictions for these volunteers ranged from 0 to 24%. In the long-term analysis, the variation of the EDAC prediction ranged from 0 to 21% probability of heavy drinking for one subject over time. Thus, mild variations of the EDAC are to be expected when the blood samples are analyzed in different laboratories. However, based on this study, these variations in the prediction of heavy drinking should not exceed >24% when using the EDAC test. This study supports the standard practice established for similar contemporary alcohol biomarkers stipulating that indications of heavy drinking become evident only when subjects experience changes of >30% in the probability of heavy drinking over time.

Bean P; Harasymiw J. The reproducibility of the Early Detection of Alcohol Consumption test using split samples analyzed in different laboratories. Alcohol and Alcoholism 46(6): 694-701, 2011. (22 refs.)

Aims: This study analyzes the reproducibility of the Early Detection of Alcohol Consumption (EDAC) test by sending blood samples obtained from nine volunteers to four different laboratories. It also describes the reproducibility of the EDAC over time by analyzing the results of testing one subject whose blood sample was sent to seven different laboratories over a 10-year period. Methods: The EDAC is a method of interpreting routine laboratory profiles to identify either binge drinking or heavy drinking; the components of the routine panel were chosen based on a best fit predictions model published previously. Results: Overall, the results of the cross-sectional analysis showed that the coefficients of variations (CVs) of the routine tests in the panel were mostly below 16%. Only three analytes (total bilirubin, aspartate aminotransferase and monocytes) showed CVs between 20 and 38%. The differences in the EDAC predictions for these volunteers ranged from 0 to 24%. In the long-term analysis, the variation of the EDAC prediction ranged from 0 to 21% probability of heavy drinking for one subject over time. Thus, mild variations of the EDAC are to be expected when the blood samples are analyzed in different laboratories. However, based on this study, these variations in the prediction of heavy drinking should not exceed > 24% when using the EDAC test. Conclusion: This study supports the standard practice established for similar contemporary alcohol biomarkers stipulating that indications of heavy drinking become evident only when subjects experience changes of > 30% in the probability of heavy drinking over time.

Bearer CF; Bailey SM; Hoek JB. Advancing alcohol biomarkers research. Alcoholism: Clinical and Experimental Research 34(6): 941-945, 2010. (14 refs.)

Biomarkers to detect past alcohol use and identify alcohol-related diseases have long been pursued as important tools for research into alcohol use disorders as well as for clinical and treatment applications and other settings. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) sponsored a workshop titled "Workshop on Biomarkers for Alcohol-Induced Disorders" in June 2008. The intent of this workshop was to review and discuss recent progress in the development and implementation of biomarkers for alcohol use and alcohol-related disorders with a goal to formulate a set of recommendations to use to stimulate and advance research progress in this critical area of alcoholism research. Presentations at this workshop reviewed the current status of alcohol biomarkers, providing a summary of the history of biomarkers and the major goals of alcohol biomarker research. Moreover, presentations provided a comprehensive overview of the current status of several well-recognized biomarkers of alcohol use, a summary of recent studies to characterize novel biomarkers and their validation, along with perspectives and experiences from other NIH institutes and from other federal agencies and industry, related to regulatory issues. Following these presentations, a panel discussion focused on a set of issues presented by the organizers of this workshop. These discussion points addressed: (i) issues related to strategies to be adopted to stimulate biomarker discovery and application, (ii) the relevance of animal studies in biomarker development and the status of biomarkers in basic science studies, and (iii) issues related to the opportunities for clinical and commercial applications. This article summarizes these perspectives and highlights topics that constituted the basis for recommendations to enhance alcohol biomarker research.

Benowitz NL; Dains KM; Dempsey D; Yu LS; Jacob P. Estimation of nicotine dose after low-level exposure using plasma and urine nicotine metabolites. Cancer Epidemiology, Biomarkers & Prevention 19(5): 1160-1166, 2010. (11 refs.)

Background: We sought to determine the optimal plasma and urine nicotine metabolites, alone or in combination, to estimate the systemic dose of nicotine after low-level exposure. Methods: We dosed 36 nonsmokers with 100, 200, or 400 mu g p.o. of deuterium-labeled nicotine (doses similar to exposure to secondhand smoke) daily for 5 days and then measured plasma and urine nicotine metabolites at various intervals over 24 hours. Results: The strongest correlations with nicotine dose were seen for the sum of four (cotinine + cotinine-glucuronide + trans-3'-hydroxycotinine + 3HC-glucuronide) or six (including also nicotine + nicotine-glucuronide) of the major nicotine metabolites in 24-hour urine collection (r = 0.96), with lesser correlations for these metabolites using spot urines corrected for creatinine at various times of day (r = 0.72-0.80). The sum of plasma cotinine + trans-3'-hydroxycotine was more highly correlated with nicotine dose than plasma cotinine alone (r = 0.82 versus 0.75). Conclusions: Our results provide guidance for the selection of biomarkers to estimate the dose of nicotine taken in low-level (secondhand smoke) tobacco exposure. Impact: This is probably relevant to active smoking as well.

Boccard J; Badoud F; Grata E; Ouertani S; Hanafi M; Mazerolles G et al. A steroidomic approach for biomarkers discovery in doping control. Forensic Science International 213(1-3): 85-94, 2011. (43 refs.)

Anti-doping authorities have high expectations of the athlete steroidal passport (ASP) for anabolic-androgenic steroids misuse detection. However, it is still limited to the monitoring of known well-established compounds and might greatly benefit from the discovery of new relevant biomarkers candidates. In this context, steroidomics opens the way to the untargeted simultaneous evaluation of a high number of compounds. Analytical platforms associating the performance of ultra-high pressure liquid chromatography (UHPLC) and the high mass-resolving power of quadrupole time-of-flight (QTOF) mass spectrometers are particularly adapted for such purpose. An untargeted steroidomic approach was proposed to analyse urine samples from a clinical trial for the discovery of relevant biomarkers of testosterone undecanoate oral intake. Automatic peak detection was performed and a filter of reference steroid metabolites mass-to-charge ratio (m/z) values was applied to the raw data to ensure the selection of a subset of steroid-related features. Chemometric tools were applied for the filtering and the analysis of UHPLC-QTOF-MSE data. Time kinetics could be assessed with N-way projections to latent structures discriminant analysis (N-PLS-DA) and a detection window was confirmed. Orthogonal projections to latent structures discriminant analysis (O-PLS-DA) classification models were evaluated in a second step to assess the predictive power of both known metabolites and unknown compounds. A shared and unique structure plot (SUS-plot) analysis was performed to select the most promising unknown candidates and receiver operating characteristic (ROC) curves were computed to assess specificity criteria applied in routine doping control. This approach underlined the pertinence to monitor both glucuronide and sulphate steroid conjugates and include them in the athletes passport, while promising biomarkers were also highlighted.

Braun JM; Daniels JL; Poole C; Olshan AF; Hornung R; Bernert JT et al. A prospective cohort study of biomarkers of prenatal tobacco smoke exposure: The correlation between serum and meconium and their association with infant birth weight. Environmental Health 9(e-53), 2010. (38 refs.)

Background: The evaluation of infant meconium as a cumulative matrix of prenatal toxicant exposure requires comparison to established biomarkers of prenatal exposure. Methods: We calculated the frequency of detection and concentration of tobacco smoke metabolites measured in meconium (nicotine, cotinine, and trans-3'-hydroxycotinine concentrations) and three serial serum cotinine concentrations taken during the latter two-thirds of pregnancy among 337 mother-infant dyads. We estimated the duration and intensity of prenatal tobacco smoke exposure using serial serum cotinine concentrations and calculated geometric mean meconium tobacco smoke metabolite concentrations according to prenatal exposure. We also compared the estimated associations between these prenatal biomarkers and infant birth weight using linear regression. Results: We detected nicotine (80%), cotinine (69%), and trans-3'-hydroxycotinine (57%) in most meconium samples. Meconium tobacco smoke metabolite concentrations were positively associated with serum cotinine concentrations and increased with the number of serum cotinine measurements consistent with secondhand or active tobacco smoke exposure. Like serum cotinine, meconium tobacco smoke metabolites were inversely associated with birth weight. Conclusions: Meconium is a useful biological matrix for measuring prenatal tobacco smoke exposure and could be used in epidemiological studies that enroll women and infants at birth. Meconium holds promise as a biological matrix for measuring the intensity and duration of environmental toxicant exposure and future studies should validate the utility of meconium using other environmental toxicants.

Comandini A; Marzano V; Curradi G; Federici G; Urbani A; Saltini C. Markers of anti-oxidant response in tobacco smoke exposed subjects: A data-mining review. (review). Pulmonary Pharmacology & Therapeutics 23(6, Special Issue): 482-492, 2010. (57 refs.)

Tobacco smoke exposure is the cause of exaggerated inflammatory responses and tissue destruction leading to chronic bronchitis and emphysema. A number of studies have used biochemical and immunological technologies to identify biomarkers of severity, risk and pharmacological target of disease. Recently, genomic and proteomic studies have been carried out to explore tobacco smoke-induced lung damage mechanisms. Eight of these studies, including 81 healthy non-smokers, 138 healthy smokers and 24 smokers with COPD, had open platform generated data available online and were reviewed in order to identify markers of smoke-induced damage by analyzing differential gene and protein expression in healthy individuals exposed to tobacco smoke in comparison with chronic obstructive pulmonary disease (COPD) smokers and healthy non-smokers. To this end the Ingenuity Pathways Analysis, a web-based application enables identifying the main biological functions and pathways, was used. The pathway most significantly associated with healthy smokers was the Nrf2-mediated Oxidative Stress Response (p-value < 0.01): out of the 22 genes/proteins identified in healthy smokers, 19 were up-regulated and three down-regulated, compared to non-smokers. Interestingly, four genes/proteins of the same pathway were differentially regulated in COPD, one up-regulated and three down-regulated, compared to healthy smokers. Moreover, in the comparison between COPD and healthy smokers, our analysis showed that the most relevant pathway was the Mitochondrial Dysfunction (p-value < 0.01) with 12 differentially regulated genes/proteins. This data-mining review supports the notion that Nrf2-regulated anti-oxidant genes play a central role in protection against tobacco smoke toxic effects and may be amenable to use as COPD risk biomarkers. Furthermore, this review suggests that mitochondrial dysfunction may be involved in the development of COPD.

Delaney-Black V; Chiodo LM; Hannigan JH; Greenwald MK; Janisse J; Patterson G et al. Just say "I don't": Lack of concordance between teen report and biological measures of drug use. Pediatrics 126(5): 887-893, 2010. (44 refs.)

BACKGROUND: Prevalence estimates of illicit drug use by teens are typically generated from confidential or anonymous self-report. While data comparing teen self-report with biological measures are limited, adult studies identify varying degrees of under-reporting. METHODS: Hair analyses for cocaine, opiates and marijuana were compared to confidential teen self-and parent-reported teen drug use in a longitudinal cohort of >400 high-risk urban teens and parents. RESULTS: Both teens and parents substantially underreported recent teen cocaine and opiate use. However, compared with parents, teens were more likely to deny biomarker-verified cocaine use. Teen specimens (hair) were 52 times more likely to identify cocaine use compared with self-report. Parent hair analyses for cocaine and opiate use were 6.5 times and 5.5 times, respectively, more likely to indicate drug use than were parental self-report. The lack of concordance between self-report and bioassay occurred despite participant's knowledge that a "certificate of confidentiality" protected both teen and adult participants, and that the biological specimens would be tested for drugs. CONCLUSIONS: These findings confirm prior reports of adult under-reporting of their own drug use while extending our understanding of teen's self-admitted drug use. The lack of concordance between teen self-or parent-reported teen drug use and biomarkers confirm our concerns that both teen-and parent-reported teen drug use is limited, at least for youth in high-risk urban settings. Methods of ascertainment other than self-or parent-report must be considered when health care providers, researchers and public health agencies attempt to estimate teen drug-use prevalence.

Dluzen DE; McDermott JL; Bourque M; Di Paolo T; Darvesh AS; Buletko AB et al. Markers associated with sex differences in methamphetamine-induced striatal dopamine neurotoxicity. Current Neuropharmacology 9(1): 40-44, 2011. (21 refs.)

Three different approaches were employed to assess various markers associated with sex differences in responses to methamphetamine ( MA). Bioassay measures reveal that MA treatment results in significantly greater reductions in body weight and increases in body temperature in male mice. Protein and mRNA determinations show significant increases in Bcl-2 and PAI-1 in male mice, while females show significant increases in GFAP and decreases in IGF-1R following treatment with MA. In mice with a heterozygous mutation of their dopamine transporter (+/- DAT), only female mice show significant differences in dopamine transporter binding and mRNA and associated reductions in striatal dopamine content along with increases in MA-evoked striatal dopamine output. The identification of these sex-dependent differences in markers provides a foundation for more exhaustive evaluation of their impact upon, and treatment of, disorders/neurotoxicity of the nigrostriatal dopaminergic system and the bases for the differences that exist between females and males.

Duka T; Trick L; Nikolaou K; Gray MA; Kempton MJ; Williams H et al. Unique brain areas associated with abstinence control are damaged in multiply detoxified alcoholics. Biological Psychiatry 70(6): 545-552, 2011. (47 refs.)

Background: The ability to abstain from drinking, despite incentives to imbibe, is essential to recovery from alcoholism. Methods: We used an incentive conflict task to investigate ability to abstain from responding during presentations of incentive cues. Both alcoholic (n = 23) and healthy subjects (n = 22) were required to withhold responding during the simultaneous presentation of two visual stimuli in which the individual presentation allowed responding for monetary reward. Brain structures activated during performance of the task were studied using functional magnetic resonance imaging in healthy volunteers (n = 8), and changes in gray matter volume were studied in a separate group of patients (n = 29) compared with control subjects (n = 31) in regions of interest identified on functional magnetic resonance imaging. Results: Abstinent alcoholic patients were severely impaired on the incentive conflict task. The impairment was greater in patients with experience of several versus a single detoxification. Healthy volunteers, during the same incentive conflict task, showed distinct patterns of brain activation (including gyrus rectus, ventromedial prefrontal cortex, and superior frontal gyrus). Reduction of gray matter volume in ventromedial prefrontal cortex and superior frontal gyrus of patients was more extensive in those with multiple detoxifications. Conclusions: Performance deficits in alcoholics are associated with withdrawal-induced impairments in prefrontal subfields, which are exacerbated following repeated episodes of detoxification. Detoxification thus compromises functional and structural integrity of prefrontal cortex and may thus impair the ability to control future drinking. Performance in the incentive conflict task is a sensitive biomarker for such deficits.

Durazzo TC; Pathak V; Gazdzinski S; Mon A; Meyerhoff DJ. Metabolite levels in the brain reward pathway discriminate those who remain abstinent from those who resume hazardous alcohol consumption after treatment for alcohol dependence. Journal of Studies on Alcohol and Drugs 71(2): 278-289, 2010. (87 refs.)

Objective: This study compared baseline metabolite levels in components of the brain reward system among individuals who remained abstinent and those who resumed hazardous alcohol consumption after treatment for alcohol dependence. Method: Fifty-one treatment-seeking alcohol-dependent individuals (abstinent for approximately 7 days [SD = 3]) and 26 light-drinking nonsmoking controls completed 1.5-T proton magnetic resonance spectroscopic imaging, yielding regional concentrations of N-acetylaspartate, choline-containing compounds, creatinc-containing compounds, and myoinositol. Metabolite levels were obtained in the following component of the brain reward system: dorsolateral prefrontal cortex, anterior cingulate cortex, insula, superior corona radiata, and cerebellar vermis. Alcohol-dependent participants were followed over a 12-month period after baseline study (i.e., at 7 days of abstinence [SD = 3]) and were classified as abstainers (no alcohol consumption; n = 18) and resumers (any alcohol consumption; n = 33) at follow-up. Baseline metabolite levels in abstainers and resumers and light-drinking nonsmoking controls were compared in the above regions of interest. Results: Resumers demonstrated significantly lower baseline N-acetylaspartate concentrations than light-drinking nonsmoking controls and abstainers in all regions of interest. Resumers also exhibited lower creatine-containing-compound concentrations than abstainers in the dorsolateral prefrontal cortex, superior corona radiata, and cerebellar vermis. Abstainers did not differ from light-drinking nonsmoking controls on baseline metabolite concentrations in any region of interest. Conclusions: The significantly decreased N-acetylaspartate and creatine-containing-compound concentrations in resumers suggest compromised neuronal integrity and abnormalities in cellular bioenergetics in major neocortical components and white-matter interconnectivity of the brain reward pathway. The lack of metabolite differences between abstainers and light-drinking nonsmoking controls suggests premorbid factors potentially contributed to the baseline brain metabolite abnormalities observed in resumers.

Ehlers CL; Phillips E; Gizer IR; Gilder DA; Wilhelmsen KC. EEG spectral phenotypes: Heritability and association with marijuana and alcohol dependence in an American Indian community study. Drug and Alcohol Dependence 106(2): 101-110, 2010. (134 refs.)

Native Americans have some of the highest rates of marijuana and alcohol use and abuse, yet neurobiological measures associated with dependence on these substances in this population remain unknown. The present investigation evaluated the heritability of spectral characteristics of the electroencephalogram (EEG) and their correlation with marijuana and alcohol dependence in an American Indian community. Participants (n = 626) were evaluated for marijuana (MJ) and alcohol (ALC) dependence, as well as other psychiatric disorders. EEGs were collected from six cortical sites and spectral power determined in five frequency hands (delta 1.0-4.0 Hz, theta 4.0-7.5 Hz, alpha 7.5-12.0 Hz, low beta 12.0-20.0 Hz and high beta/gamma 20-50 Hz). The estimated heritability (112) of the EEG phenotypes was calculated using SOLAR, and ranged from 0.16 to 0.67. Stepwise linear regression was used to detect correlations between MJ and ALC dependence and the spectral characteristics of the EEG using a model that took into account: age, gender, Native American Heritage (NAH) and a lifetime diagnosis of antisocial personality and/or conduct disorder (ASPD/CD). Increases in spectral power in the delta frequency range, were significantly correlated with gender (p < 0.001) and marijuana dependence (p < 0.003). Gender, age, NAH and ASPD/CD were all significantly (p < 0.001) correlated with theta, alpha and beta band power, whereas alcohol dependence (p < 0.01), gender (p < 0.001), and ASPD/CD (p < 0.001) were all correlated with high beta/gamma band power. These data suggest that the traits of EEG delta and high beta/gamma activity are correlated with MJ dependence and alcohol dependence, respectively, in this community sample of Native Americans.

El-Haj BM; Ali HS; Hamoudi NM. Oripavine as a new marker of opiate product use. Forensic Toxicology 29(2): 152-158, 2011. (21 refs.)

During our extensive surveillance of opiates in urine specimens of opium users, we noticed the appearance of an unknown peak (compound X) in total ion chromatograms obtained by gas chromatography-mass spectrometry (GC-MS) after enzymatic hydrolysis and trimethylsilyl (TMS) derivatization. We identified the compound X as oripavine. Oripavine was found to be a new and useful putative marker of opium/poppy seed use in differentiation from heroin, pharmaceutical codeine, and pharmaceutical morphine use. The presence of oripavine in the urine of opium users is probably the result of O-demethylation of the opium alkaloid thebaine. Analytical method optimization for GC-MS detection of oripavine in urine was also undertaken. Underivatized oripavine could not be detected by GC-MS, and trials for derivatization of oripavine with acetic anhydride and propionic anhydride were unsuccessful. Trials were successful with bis(trimethylsilyl)trifluoroacetamide/trimethylchlorosilane. It was also disclosed that almost all amounts of oripavine in human urine existed in the unconjugated form; it was absolutely necessary to hydrolyze the conjugate before TMS derivatization of oripavine for its GC-MS analysis.

Fidler JA; Stapleton JA; West R. Variation in saliva cotinine as a function of self-reported attempts to reduce cigarette consumption. Psychopharmacology 217(4): 587-593, 2011. (22 refs.)

Rationale: Cotinine is an accurate objective marker of nicotine intake. There is very little information on its stability over time or as a function of self-reported attempts at smoking reduction. Objectives: This study aimed to assess the stability of saliva cotinine concentrations over a 3-month period, as a function of self-reported attempts to reduce cigarette consumption, using data from a general population sample of English smokers. Methods: Six-hundred and ninety-one smokers from a population sample of English smokers provided saliva samples for cotinine analysis on two occasions 3 months apart. Data on cigarette consumption, whether smokers reported that they were attempting to cut down consumption and concurrent use of nicotine replacement therapy (NRT), were also collected on both occasions. Results The 'test-retest' measure of cotinine stability was 0.76, and the simple correlation was 0.73. Smokers not using NRT who reported cutting down on one occasion but not the other showed a small reduction in cigarette consumption at the time they were cutting down (1.1 cig per day, p=0.013) but no significant difference in saliva cotinine concentrations (mean reduction=13.4 ng/ml, p=0.39). Conclusions: Saliva cotinine concentrations show moderate-to-high stability within subjects over a 3-month period. Smokers' reports of attempting to cut down their smoking are associated with small daily cigarette consumption decreases but no detectable change in nicotine intake.

Freeman WM; Salzberg AC; Gonzales SW; Grant KA; Vrana KE. Classification of alcohol abuse by plasma protein biomarkers. Biological Psychiatry 68(3): 219-222, 2010. (20 refs.)

Background: Biochemical diagnostics of ethanol intake would improve alcohol abuse treatment and have applications in clinical trial and public safety settings. Self-reporting of alcohol use has clinical utility but lacks the desired reliability. Previously, proposed single-analyte biochemical tests of alcohol intake suffer from low sensitivity and specificity or examine only acute drinking and have therefore seen limited clinical use. Methods: To address this unmet need, plasma protein biomarker discovery and validation were performed with an alcohol self-administering nonhuman primate model system to develop a diagnostic that accurately classifies subjects into nondrinking, nonabusive drinking, and abusive drinking categories. Results: A 17-plasma protein panel was determined that correctly classifies abusive drinking with 100% sensitivity and also differentiates any level of drinking from alcohol abstinence with 88% accuracy. Conclusions: The biomarker panel reflects changes in multiple organ systems and suggests robust changes in the plasma proteome with drinking that might serve as a sensitive and specific diagnostic test. The specific plasma proteins altered with alcohol self-administration might represent indicators of alcohol-induced stress on a variety of organ systems.

Freeman WM; Vrana KE. Future prospects for biomarkers of alcohol consumption and alcohol-induced disorders. Alcoholism: Clinical and Experimental Research 34(6): 946-954, 2010. (55 refs.)

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis, treatment, and research of alcohol abuse and alcoholism. Successful development of a biomarker that allows for accurate assessment of alcohol intake and drinking patterns would not only be a major advance in clinical care but also a valuable research tool. A number of advances have been made in testing the validity of proposed biomarkers as well as in identifying potential new biomarkers through systems biology approaches. This commentary will examine the definition of a biomarker of heavy drinking, the types of potential biomarkers, the steps in biomarker development, the current state of biomarker development, and critical obstacles for the field. The challenges in developing biomarkers for alcohol treatment and research are similar to those found in other fields. However, the alcohol research field must reach a competitive level of rigor and organization. We recommend that NIAAA consider taking a leadership role in organizing investigators in the field and providing a common set of clinical specimens for biomarker validation studies.

Frost-Pineda K; Liang QW; Liu JM; Rimmer L; Jin Y et al. Biomarkers of potential harm among adult smokers and nonsmokers in the total exposure study. Nicotine & Tobacco Research 13(3): 182- 193, 2011. (51 refs.)

There is overwhelming medical and scientific consensus that cigarette smoking causes lung cancer, heart disease, emphysema, and other serious diseases in smokers. In the Total Exposure Study, 29 biomarkers of potential harm (BOPH) were measured in a cross-sectional sample of 3,585 adult smokers (AS) and 1,077 nonsmokers (NS). The BOPH included markers of oxidative stress, inflammation, platelet activation, endothelial function, lipid metabolism, hematology, metabolism, the cardiovascular system, lung function, kidney function, and liver function. Multiple stepwise regression was used to examine the effect of demographic factors (age, gender, body mass index [BMI], and race) and smoking (number of cigarettes smoked per day or nicotine equivalents [NE] per 24 hr and smoking duration) on each BOPH. As compared with NS, AS had > 10% higher levels of 8-epi-prostaglandin F-2 alpha (8-epi-PG F-2 alpha, 42%), 11-dehydrothromboxane B-2 (11-DHTB, 29%), white blood cell (WBC) count (19%), high-sensitivity C-reactive protein (15%), triglycerides (16%), and alkaline phosphatase (11%) and had 18% lower total bilirubin. Multiple stepwise regression revealed that although NE (milligrams per 24 hours) was statistically significant for 18 of the 29 BOPH, it was the most important factor only for WBCs and 11-DHTB. Smoking duration was the most important factor for forced expiratory volume in 1 second. In contrast, BMI was the most important factor for 12 BOPH. These results contribute to the understanding of the relationship between tobacco smoking and potential biological effects.

Fu M; Martinez-Sanchez JM; Agudo A; Pascual JA; Borras JM; Samet JM et al. Association between time to first cigarette after waking up and salivary cotinine concentration. Nicotine & Tobacco Research 13(3): 168-172, 2011. (24 refs.)

The time to first cigarette smoked after waking up appears to be a good predictor of plasma and urine cotinine levels; however, collection of blood and urine is difficult in population-based studies and may influence participation. We aimed to test whether time to first cigarette is associated with salivary cotinine. We used data from a cross-sectional study on a representative sample of the general population of Barcelona, Spain. We gathered information on smoking by means of a questionnaire and collected saliva for cotinine analysis. Of 1,245 participants, 22.9% were daily smokers, and the final sample for analysis consisted of 210 daily smokers. There were significant associations between salivary cotinine and time to first cigarette, between cigarette consumption and time to first cigarette, and between salivary cotinine and cigarette consumption. Salivary cotinine had decreased as time to first cigarette increased. After adjusting for cigarette consumption and sex, there were significant differences in mean salivary cotinine according to time to first cigarette (< 5 min: 219.2 ng/ml; 6-30 min: 175.8 ng/ml; 31-60 min: 168.5 ng/ml; > 60 min: 137.2 ng/ml). All paired comparisons were significant (p < .001) except in the 6- to 30-min group versus the 31- to 60-min group (p = .701). After adjustment for the number of cigarettes smoked in the last 24 hr, time to first cigarette is associated with salivary cotinine concentration.

Fukushima W; Miyake Y; Tanaka K; Sasaki S; Kiyohara C; Tsuboi Y et al. Alcohol drinking and risk of Parkinson's disease: A case-control study in Japan. BMC Neurology 10: e-article 111, 2010. (33 refs.)

Background: Although some epidemiologic studies found inverse associations between alcohol drinking and Parkinson's disease (PD), the majority of studies found no such significant associations. Additionally, there is only limited research into the possible interactions of alcohol intake with aldehyde dehydrogenase (ALDH) 2 activity with respect to PD risk. We examined the relationship between alcohol intake and PD among Japanese subjects using data from a case-control study. Methods: From 214 cases within 6 years of PD onset and 327 controls without neurodegenerative disease, we collected information on "peak", as opposed to average, alcohol drinking frequency and peak drinking amounts during a subject's lifetime. Alcohol flushing status was evaluated via questions, as a means of detecting inactive ALHD2. The multivariate model included adjustments for sex, age, region of residence, smoking, years of education, body mass index, alcohol flushing status, presence of selected medication histories, and several dietary factors. Results: Alcohol intake during peak drinking periods, regardless of frequency or amount, was not associated with PD. However, when we assessed daily ethanol intake separately for each type of alcohol, only Japanese sake (rice wine) was significantly associated with PD (adjusted odds ratio of >= 66.0 g ethanol per day: 3.39, 95% confidence interval: 1.10-11.0, P for trend = 0.001). There was no significant interaction of alcohol intake with flushing status in relation to PD risk. Conclusions: We did not find significant associations between alcohol intake and PD, except for the daily amount of Japanese sake. Effect modifications by alcohol flushing status were not observed.

Gray TR; Eiden RD; Leonard KE; Connors G; Shisler S; Huestis MA. Nicotine and metabolites in meconium as evidence of maternal cigarette smoking during pregnancy and predictors of neonatal growth deficits. Nicotine & Tobacco Research 12(6): 658-664, 2010. (29 refs.)

Many women continue tobacco use during pregnancy despite known adverse consequences on neonatal growth and development. Testing meconium, the first neonatal feces, for tobacco biomarkers offers objective evidence of prenatal tobacco exposure. However, relationships between the amount, frequency, and timing of cigarette smoking during gestation and tobacco biomarker meconium concentrations and neonatal outcomes are unclear. Eighty-seven pregnant women provided detailed self-reports of daily tobacco consumption throughout pregnancy. Nicotine, cotinine, and trans-3'-hydroxycotinine were quantified in neonatal meconium by liquid chromatography-tandem mass spectrometry. Among nonsmokers, all meconium specimens were negative, whereas nearly all meconium specimens were positive if the mother self-reported tobacco use into the third trimester. Tobacco biomarker concentrations were significantly albeit weakly correlated with mean cigarettes per day in the third trimester. Reduced birth weight, gestational age, or head circumference were observed if meconium contained one or more tobacco biomarkers, but deficits did not correlate with biomarker concentrations. While previously thought to reflect second and third trimester drug exposure, meconium appears to reliably identify only third trimester drug use. While a 10 ng/g nicotine, cotinine, or trans-3'-hydroxycotinine cutoff in meconium was previously proposed to differentiate tobacco-exposed from nonexposed or passively exposed neonates, improved maternal self-reporting techniques in this cohort suggest that a lower cutoff, equivalent to the analytic limits of quantification, is more appropriate.

Guardia-Serecigni J; Estorch M; Surkov S; Camacho MD; Garcia-Ribas G. Multidimensional alcohol craving scale and [123I] Iodobenzamide SPECT as predictors of early relapse in alcohol-dependent patients. Adicciones 23(2): 157-164, 2011. (23 refs.)

Background: The Multidimensional Alcohol Craving Scale (MACS) and Single Photon Emission Computerized Tomography (SPECT) with I-123-iodobenzamide (I-123-IBZM) can be useful tools for assessing relapse risk in early recovery from alcohol-dependency. The aim of this study was to assess possible relationships between MACS score, I-123-IBZM binding and time to first heavy drinking day (TFHD) after detoxification treatment. Methods: Nineteen alcohol-dependent in-patients were evaluated by MACS scale and an I-123-IBZM-SPECT, performed following alcohol detoxification treatment. At discharge, participants were advised to take naltrexone 50 mg/day for relapse prevention. TFHD was assessed over a 12-week follow up. Results: The MACS score at the beginning of the detoxification process and naltrexone treatment after detoxification were independent predictive factors for TFHD. Conclusions: The MACS scale is a better predictor of TFHD than IBZM binding. It is simple, non-invasive and inexpensive and appears to be a useful instrument both for clinical practice and for research.

Hong LE; Hodgkinson CA; Yang YH; Sampath H; Ross TJ; Buchholz B et al. A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction. Proceedings of the National Academy of Sciences of the United States of America 107(30): 13509-13514, 2010. (56 refs.)

Whole-genome searches have identified nicotinic acetylcholine receptor alpha 5-alpha 3-beta 4 subunit gene variants that are associated with smoking. How genes support this addictive and high-risk behavior through their expression in the brain remains poorly understood. Here we show that a key alpha 5 gene variant Asp398Asn is associated with a dorsal anterior cingulate-ventral striatum/extended amygdala circuit, such that the "risk allele" decreases the intrinsic resting functional connectivity strength in this circuit. Importantly, this effect is observed independently in nonsmokers and smokers, although the circuit strength distinguishes smokers from nonsmokers, predicts addiction severity in smokers, and is not secondary to smoking per se, thus representing a trait-like circuitry biomarker. This same circuit is further impaired in people with mental illnesses, who have the highest rate of smoking. Identifying where and how brain circuits link genes to smoking provides practical neural circuitry targets for new treatment development.

Hsieh SJ; Ware LB; Eisner MD; Yu L; Jacob P; Havel C et al. Biomarkers increase detection of active smoking and secondhand smoke exposure in critically ill patients. Critical Care Medicine 39(1): 40-45, 2011. (31 refs.)

Objectives: The association between tobacco smoke exposure and critical illness is not well studied, largely because obtaining an accurate smoking history from critically ill patients is difficult. Biomarkers can provide quantitative data on active and secondhand cigarette smoke exposure. We sought to compare cigarette smoke exposure as measured by biomarkers to exposure by self-report in a cohort of critically ill patients and to determine how well biomarkers of cigarette smoke exposure correlate with each other in this population. Design, Setting, and Patients: Serum and urine cotinine and trans-3'-hydroxycotinine, urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and hair and nail nicotine levels were measured in 60 subjects enrolled in an observational cohort of critically ill subjects at a tertiary academic medical center in Tennessee. Smoking history was obtained from patients, their surrogates, or the medical chart. Cigarette smoke exposure as measured by biomarkers was compared to exposure by history. Measurements and Main Results: By smoking history, 29 subjects were identified as smokers, 28 were identified as nonsmokers, and 3 were identified as unknown. The combination of serum cotinine and urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol identified 27 of the 28 nonsmokers by history either as active smokers (n = 6, 21%) or as exposed to secondhand smoke (n = 21, 75%). All biomarker levels were strongly correlated with each other (r = .69-.95, p < .0001). Conclusions: The combination of serum cotinine and urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol identified considerably more active smokers than did smoking history and detected a high prevalence of secondhand smoke exposure in a critically ill population. These markers will be important for future studies investigating the relationship between active smoking and secondhand smoke exposure and critical illness.

Huang YC; Zhang J; Li DL; Dai Y; Wang CG; Ma KY et al. Circulating biomarkers of hazard effects from cigarette smoking. Toxicology and Industrial Health 27(6): 531-535, 2011. (33 refs.)

Smoking, leading to over 438,000 annual deaths in the US and 92 billion US dollars in lost productivity, is an important risk factor for several diseases. Global smoking statistics for 2002 have shown that 80,000 to 100,000 children worldwide start smoking every day. Human biomonitoring nowadays has provided an efficient and cost-effective means of measuring human exposures and biological effects of smoking. To review the utility of biomarkers in reflecting the hazard from cigarette smoking, we comprehensively searched the Cochrane Library, Medline and EMbase from 1966 to May 2010 with the language limit of English. We found that the currently used biomarkers, such as tobacco-specific metabolites, smoking-induced genotoxic products, may not scientifically reflect the hazard from cigarette smoking. More research is needed to find out more effective biomarkers for estimating hazards from cigarette smoking. This paper is expected to help researchers understand the current utilization of biomarkers related to cigarette smoking and to provide suggestive guides to tobacco companies in producing less-toxic cigarettes, thus to provide a safe way to smoke.

Iacono WG; Malone SM. Developmental endophenotypes: Indexing genetic risk for substance abuse with the p300 brain event-related potential. Child Development Perspectives 5(4): 239-247, 2011. (72 refs.)

Although substance use disorders (SUDs) are heritable, their complexity has made identifying genes underlying their development challenging. Endophenotypes, biologically informed quantitative measures that index genetic risk for a disorder, are being recognized for their potential to assist the search for disorder-relevant genes. After outlining criteria for an endophenotype that includes developmental considerations, this article reviews how the brain P300 response serves as an index of genetic risk for substance abuse and related externalizing disorders. The P300 response is highly heritable and associated broadly with characteristics of externalizing disorder, including childhood disruptive disorders, antisociality, and precocious expression of deviant behavior. This association appears to be mediated by shared genetic influences. Prospective studies confirm that reduced P300 amplitude present in youth prior to significant exposure to addictive substances is associated with the subsequent development of SUDs. Despite pronounced change in mean level over the course of development, P300 amplitude shows strong rank-order stability with repeated assessment through young adulthood. In addition, P300 developmental trajectories based on multiple assessments show very high heritability and may be especially informative as measures of genetic risk. Collectively, these findings provide strong support for the idea that P300 amplitude and its change through development reflect genetic vulnerability to substance abuse and related externalizing psychopathology.

Julius BR; Ward BA; Stein JH; McBride PE; Fiore MC; Colbert LH. Ambulatory activity associations with cardiovascular and metabolic risk factors in smokers. Journal of Physical Activity & Health 8(7): 994-1003, 2011. (48 refs.)

Background: We examined the association between ambulatory activity and biological markers of health in smokers. Methods: Baseline data from 985 subjects enrolled in a pharmacologic smoking cessation trial were examined. Body size, blood pressure, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), total and small LDL particles, LDL size, high density lipoprotein cholesterol, triglycerides (TG), C-reactive protein (CRP), creatinine, fasting glucose, and hemoglobin A1c were assessed in relation to pedometer-assessed ambulatory activity, as was the odds of metabolic syndrome and CRP > 3 mg/L. Effect modification by gender was examined. Results: Only waist circumference was lower with greater steps/day in the men and women combined (P(trend) < 0.001). No other significant relationships were noted in men, while women with >= 7500 steps/day had lower weight, BMI, CRP, TG, total, and small LDL particles compared with those with < 7500 steps/day. These women also had 62% and 43% lower odds of metabolic syndrome and elevated CRP, respectively, compared with the less active women. Adjustment for BMI attenuated all the associations seen in women. Conclusions: Greater ambulatory activity is associated with lower levels of metabolic and cardiovascular risk factors in female smokers which may, in part, be mediated by a reduction in BMI.

Kapusta ND; Pietschnig J; Plener PL; Bluml V; Lesch OM; Walter H. Does breath carbon monoxide measure nicotine dependence? Journal of Addictive Diseases 29(4): 493-499, 2010. (62 refs.)

The aim of the current study was the examination of exhaled breath carbon monoxide levels as a predictor for heaviness of smoking. In this regard, nicotine dependence was assessed among a representative sample of 1,870 Austrian male military conscripts in a cross-sectional setting. Participants completed the Heaviness of Smoking Index (a brief questionnaire for assessment of nicotine dependence), and their expired breath carbon monoxide levels were measured. The performance of carbon monoxide as a predictor of dependence levels was examined by means of Receiver-Operating-Characteristic Curve . Area Under the Curve, as well as sensitivity and specificity, were reported for each carbon monoxide cut-off level. The authors demonstrate that exhaled carbon monoxide levels serve as a satisfactory means to discriminate between smokers and non-smokers, yielding optimal discrimination at a cut-off level epsilon 5.5 parts per million (ppm), with a sensitivity of 95% and a specificity of 83%. However, the results indicate that carbon monoxide levels do not discriminate adequately between different levels of severity of nicotine dependence. The study demonstrates exhaled carbon monoxide as a useful marker of smoking status but not of nicotine dependence.

Kassim S; Islam S; Croucher RE. Correlates of nicotine dependence in UK resident Yemeni Khat chewers: A cross-sectional study. Nicotine & Tobacco Research 13(12): 1240-1249, 2011. (73 refs.)

Khat chewing is often associated with tobacco use with impacts on health. This cross-sectional study aimed (a) to explore and validate aspects of self-reported tobacco smoking and whether objective measures of tobacco smoking differ in different situations among khat chewers who smoked and (b) to assess the social factors correlated with nicotine dependence among khat chewers who smoked regularly. This study recruited a purposive sample of 204 U.K. resident Yemeni khat chewers during random visits to Khat sale outlets. Data were collected via a face-to-face scheduled interview. Data analyses included descriptive tests and a hierarchical linear multiple regression. Of 133 self-reported tobacco smokers, 68% were regular smokers with a mean (SD) carbon monoxide (CO) score (20.53 +/- 12.12 ppm) and 32% were episodic smokers with a mean (SD) CO score (16 +/- 15.66 ppm). Tobacco smoking as an enhancement of the impacts of khat chewing was reported by 65% and 69% of regular and episodic smokers, respectively. In both groups, higher CO scores were recorded during khat chewing. Hierarchical linear multiple regression modeling showed that increases in levels of severity of dependence on khat chewing were correlated positively with increase in levels of nicotine dependence (beta = .27, p = .006, 95% CI = 0.05, 0.29), whereas social participation was correlated inversely (beta = -.34, p = .001, 95% CI = -0.06, -0.02). In this study, smoking prevalence was high. Smoking increased during khat chewing. Nicotine dependence levels correlated positively with khat dependence levels, while higher social participation reduced nicotine dependence.

Kravos M; Malesic I. Glutamate dehydrogenase as a marker of alcohol dependence. Alcohol and Alcoholism 45(1): 39-44, 2010. (35 refs.)

Aims: The aim of this study was to examine glutamate dehydrogenase (GLDH) in the diagnostic combinations as a result of new findings. Methods: GLDH, gama-glutamyltransferase (GGT), aspartate-aminotranferase (AST), alanine-aminotransferase (ALT) and erythrocyte mean cell volume (MCV) were assessed three times in 238 alcoholics admitted to hospital: on admission, after 24 h and after 7 days. Results: All the values were significantly higher than those in healthy persons. The fastest activity decrease was seen in GLDH. The kinetics of GLDH and AST were more applicable than GGT kinetics after a week, but GLDH kinetics were most reliable. GLDH was the most specific laboratory marker with almost 90% specificity. The sensitivity of combination MCV and GLDH kinetics after 1 week of abstinence was pathognomonic by 97.2%. This decision tree gave us a model with 84.5% accuracy. Conclusions: GLDH is an equally accurate marker of alcoholism in comparison to others, if its significantly faster decrease is taken into consideration. We strongly believe that watching changes in the activity of laboratory markers of alcoholism is an effective yet overlooked aid.

Kulaga V; Gareri J; Fulga N; Koren G. Agreement between the fatty acid ethyl ester hair test for alcohol and social workers' reports. Therapeutic Drug Monitoring 32(3): 294-299, 2010. (59 refs.)

The purpose of this study was to examine the relationship between social worker reports and the fatty acid ethyl ester (FAEE) test as a biomarker for heavy alcohol use. In 2005, a diagnostic program to detect excessive alcohol use by FAEE hair analysis in parents at high risk of having children with fetal alcohol spectrum disorders was established. All cases submitted by Child Protective Services between May and December of 2007 (n = 172) were included comparing social worker reports with FAEE test outcome by odds ratio analysis. A subanalysis of mothers (n = 119), excluding fathers, was also performed. Factors associated with testing positive for hair FAEE in parents, and mothers alone, were: knowledge of a specific instance of problem drinking within the past 6 months (odds ratio [OR] = 5.11, 2.57-10.16 and OR = 8.51, 3.59-20.18, respectively) and third party reports alleging alcohol abuse (OR = 3.31, 1.69-6.46 and OR = 3.30, 1.45-7.50, respectively). Mothers who admitted to heavy drinking were also seven times more likely to test positive for hair FAEE (OR = 6.74, 1.50-30.38) than those who did not. Factors negatively associated with testing positive for hair FAEE in parents, and mothers alone, were: social workers testing for FAEE without the suspicion of alcohol use but rather as a measure to "cover all bases'' (OR = 0.09, 0.02-0.40 and (OR = 0.13, 0.03-0.58, respectively) or because of a history/suspicion of illicit drug use (OR = 0.2, 0.07-0.55 and OR = 0.26, 0.08-0.80, respectively). Eleven of 15 reports, indicating levels of consumption, were also in clinical agreement with FAEE test outcome. The FAEE hair test is being applied for the first time in the present context. Our results show the test corroborates well with social workers' suspicion of alcohol use. Reported factors directly related to alcohol use were significantly associated with testing positive for excessive alcohol use, whereas factors not directly related to alcohol use were negatively associated with testing positive.

Li CSR; Morgan PT; Matuskey D; Abdelghany O; Luo X; Chang JLK et al. Biological markers of the effects of intravenous methylphenidate on improving inhibitory control in cocaine-dependent patients. Proceedings of the National Academy of Sciences of the United States of America 107(32): 14455-14459, 2010. (75 refs.)

Prior research points to the importance of psychostimulants in improving self-control. However, the neural substrates underlying such improvement remain unclear. Here, in a pharmacological functional MRI study of the stop signal task, we show that methylphenidate (as compared with placebo) robustly decreased stop signal reaction time (SSRT), an index of improved control, in cocaine-dependent patients (a population in which inhibitory control is impaired). Methylphenidate-induced decreases in SSRT were positively correlated with inhibition-related activation of left middle frontal cortex (MFC) and negatively with activation of the ventromedial prefrontal cortex (vmPFC) in whole brain linear regressions. Inhibition-related MFC but not vmPFC activation distinguished individuals with short and long SSRT in 36 demographically matched healthy individuals, whereas vmPFC but not MFC activation, along with improvement in SSRT, was correlated with a previously implicated biomarker of methylphenidate response (systolic blood pressure). These results implicate a specific neural (i.e., vmPFC) mechanism whereby stimulants improve inhibitory control. Altered ventromedial prefrontal activation and increased blood pressure may represent useful CNS and peripheral biomarkers in individualized treatment with methylphenidate for patients with cocaine dependence.

Li LH; Everhart T; Jacob P; Jones R; Mendelson J. Stereoselectivity in the human metabolism of methamphetamine. British Journal of Clinical Pharmacology 69(2): 187-192, 2010. (17 refs.)

AIM: To characterize the formation and urinary elimination of metabolites of S-(+) and R-(-) methamphetamine (MA) in humans. METHODS: In this 12-subject, six-session, double-blind, placebo-controlled, balanced, crossover design study, the formation of the MA metabolites para hydroxymethamphetamine (pOH-MA) and amphetamine (AMP) were determined in urine after intravenous doses of S-(+)-MA 0.25 and 0.5 mg kg(-1), R-(-)-MA 0.25 and 0.5 mg kg(-1), racemic MA 0.5 mg kg(-1), or placebo. Parent drug and metabolite levels in urine and plasma were measured by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental models using WinNonlin. RESULTS: An approximately threefold enantioselectivity difference in elimination was observed for AMP, with 7% of the dose converted to S-(+)-AMP vs. 2% to R-(-)-AMP (P < 0.001). Furthermore, less R-(-)-pOH-MA was excreted in the urine compared with S-(+)-pOH-MA (8% vs. 11%, P = 0.02). Correspondingly, S-(+)-MA excretion was less than R-(-)-MA (42% vs. 52%; P = 0.005). CONCLUSIONS: The metabolism of MA is enantioselective, with formation of AMP having the highest isomer selectivity. A greater percentage of MA is converted to pOH-MA (8-11%) than AMP (2-7%). The formation of pOH-MA was less affected by the MA enantiomer administered, suggesting that urine pOH-MA may be a more stable biomarker of MA metabolism.

Li LH; Lopez JC; Galloway GP; Baggott MJ; Everhart T; Mendelson J. Estimating the intake of abused methamphetamines using experimenter-administered deuterium labeled r-methamphetamine: Selection of the r-methamphetamine dose. Therapeutic Drug Monitoring 32(4): 504-507, 2010. (9 refs.)

All addictive drugs produce tolerance and addicts compensate by increasing drug exposure. Thus, the quantity of illicit drug ingested is related to the severity of addiction. Unfortunately, there are no objective methods to estimate intake for most addictive drugs. Using experimenter-administered doses of deuterium-labeled R-methamphetamine (R-[-]-MA-d3), we have developed a method to estimate the amount of abused methamphetamine intake in addicts enrolled in clinical trials. This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of single oral doses of R-MA in healthy adults to select a dose of R-MA-d3 to be used as a biomarker for estimation the amount of methamphetamine abuse. This was a five-session randomized, double-blind, placebo-controlled, balanced crossover study in eight subjects. Oral R-(-)-MA was dosed at 0 mg, 1 mg, 2.5 mg, 5 mg, or 10 mg; bioavailability was estimated by slow intravenous dosing (30 minutes) of 2.5 mg R-(-)-MA-d3 given with the 2.5 mg R-(-)-MA oral dose condition. Pharmacokinetic and pharmacodynamic measures were obtained. No serious adverse events occurred during the study and all doses of R-MA were well tolerated. Linear pharmacokinetics was observed within our oral dose range of 1 to 10 mg. Complete bioavailability and pharmacologic inactivity were found for all oral doses. These characteristics indicate the advantage of using a small oral R-(-)-MA-d3 dose as a biomarker to estimate exposure to abused methamphetamine. Based on these results, 5 mg R-(-)-MA-d3 has been selected as the biomarker dose in future studies. Preliminary findings from our study indicate that experimenter-administered oral R-(-)-MA-d3 may allow estimation of abused methamphetamine intake and exposure. Knowledge of the quantity of methamphetamine intake may allow better estimation of disease severity and treatment efficacy. Experience gained from this study also can be applied to the management of other drug dependence problems such as cocaine, cannabinoid, and opiate addiction.

Liangpunsakul S; Qi R; Crabb DW; Witzmann F. Relationship between alcohol drinking and spartate minotransferase: Alanine minotransferase (AST:ALT) Ratio, Mean Corpuscular Volume (MCV), Gamma-Glutamyl Transpeptidase (GGT), and Apolipoprotein A1 and B in the US Population. Journal of Studies on Alcohol and Drugs 71(2): 249-252, 2010. (8 refs.)

Objective: The misuse of alcohol, even at levels just above two drinks per day, is a public health problem, but identifying patients with this potentially unhealthy drinking is hindered by the lack of tests. Several blood tests, such as those testing for gamma-glutamyl transpeptidase (GGT) or mean corpuscular volume (MCV), are among the commonly used markers to identify very heavy drinking, but combinations of these markers have rarely been tested in lighter drinkers. We examined the relationship between alcohol drinking and the levels of these markers in a national population-based study composed primarily of lighter drinkers. Method: Data were analyzed from 8,708 adult participants in the third U.S. National Health and Nutrition Examination Survey after excluding subjects with iron overload; with hepatitis B and C; who were pregnant; and who were taking prescription drugs such as phenytoin (Dilantin), barbiturates, and hydroxyurea (Droxia and Hydrea). The relationship between the amount of alcohol drinking and GGT, aspartate aminotransferase:alanine aminotransferase ratio, MCV of erythrocytes, and apolipoprotein A1 and B were analyzed and adjusted for potential liver injury risk factors. Results: The prevalence of unhealthy alcohol drinking (defined as consumption of more than two standard drinks per day) was 6.7%. Heavier drinkers tended to be younger and reported an average of 4.2 drinks per day. When tested alone or in combination, the sensitivity and positive predictive values for these blood tests were too low to be clinically useful in identifying the subjects in the heavier drinking category. Conclusions: In this large, national, population-based study, the markers of heavy drinking studied here, either alone or in combination, did not appear to be useful in identifying unhealthy drinking. More work is needed to find the novel marker(s) associated with risky alcohol drinking.

Liu JM; Liang QW; Frost-Pineda K; Muhammad-Kah R; Rimmer L; Roethig H et al. Relationship between biomarkers of cigarette smoke exposure and biomarkers of inflammation, oxidative stress, and platelet activation in adult cigarette smokers. Cancer Epidemiology, Biomarkers & Prevention 20(8): 1760-1769, 2011. (55 refs.)

Background: Cigarette smoking is a risk factor for several diseases, including cardiovascular disease, chronic obstructive pulmonary disease, and lung cancer, but the role of specific smoke constituents in these diseases has not been clearly established. Methods: The relationships between biomarkers of potential harm (BOPH), associated with inflammation [white blood cell (WBC), high sensitivity C-reactive protein (hs-CRP), fibrinogen, and von Willebrand factor (vWF)], oxidative stress [8-epi-prostaglandin F(2 alpha) (8-epiPGF(2 alpha))] and platelet activation [11-dehydro-thromboxin B(2) (11-dehTxB(2))], and machine-measured tar yields (grouped into four categories), biomarkers of exposure (BOE) to cigarette smoke: nicotine and its five metabolites (nicotine equivalents), 4-methylnitrosamino-1-(3-pyridyl)-1-butanol(total NNAL), carboxyhemoglobin, 1-hydroxypyrene, 3-hydroxypropylmercapturic acid, and monohydroxybutenyl-mercapturic acid, were investigated in 3,585 adult smokers and 1,077 nonsmokers. Results: Overall, adult smokers had higher levels of BOPHs than nonsmokers. Body mass index (BMI), smoking duration, tar category, and some of the BOEs were significant factors in the multiple regression models. Based on the F value, BMI was the highest ranking factor in the models for WBC, hs-CRP, fibrinogen, and 8-epiPGF(2 alpha), respectively, and gender and smoking duration for 11-dehTxB(2) and vWF, respectively. Conclusions: Although several demographic factors and some BOEs were statistically significant in the model, the R(2) values indicate that only up to 22% of the variability can be explained by these factors, reflecting the complexity and multifactorial nature of the disease mechanisms. Impact: The relationships between the BOEs and BOPHs observed in this study may help with the identification of appropriate biomarkers and improve the design of clinical studies in smokers.

Marques P; Tippetts S; Allen J; Javors M; Alling C; Yegles M et al. Estimating driver risk using alcohol biomarkers, interlock blood alcohol concentration tests and psychometric assessments: Initial descriptives. Addiction 105(2): 226-239, 2010. (48 refs.)

Aim: To identify alcohol biomarker and psychometric measures that relate to drivers' blood alcohol concentration (BAC) patterns from ignition interlock devices (IIDs). Design, setting, participants, measurements In Alberta, Canada, 534 drivers, convicted of driving under the influence of alcohol (DUI), installed IIDs and agreed to participate in a research study. IID BAC tests are an established proxy for predicting future DUI convictions. Three risk groups were defined by rates of failed BAC tests. Program entry and follow-up blood samples (n = 302, 171) were used to measure phosphatidyl ethanol (PETH), carbohydrate deficient transferrin (%CDT), gamma glutamyltransferase (GGT) and other biomarkers. Program entry urine (n = 130) was analyzed for ethyl glucuronide (ETG) and ethyl sulphate (ETS). Entry hair samples were tested for fatty acid ethyl esters (FAEE) (n = 92) and ETG (n = 146). Psychometric measures included the DSM-4 Diagnostic Interview Schedule Alcohol Module, Alcohol Use Disorders Identification Test (AUDIT), the time-line follow-back (TLFB), the Drinker Inventory of Consequences (DRINC) and the Temptation and Restraint Inventory (TRI). Findings: Except for FAEE, all alcohol biomarkers were related significantly to the interlock BAC test profiles; higher marker levels predicted higher rates of interlock BAC test failures. PETH, the strongest with an overall analysis of variance F ratio of 35.5, had significant correlations with all nine of the other alcohol biomarkers and with 16 of 19 psychometric variables. Urine ETG and ETS were correlated strongly with the IID BAC tests. Conclusions The findings suggest that several alcohol biomarkers and assessments could play an important role in the prediction and control of driver alcohol risk when re-licensing.

Mashhoon Y; Janes AC; Jensen JE; Prescot AP; Pachas G; Renshaw PF et al. Anterior cingulate proton spectroscopy glutamate levels differ as a function of smoking cessation outcome. (review). Progress In Neuro-Psychopharmacology & Biological Psychiatry 35(7): 1709-1713, 2011. (29 refs.)

Background: Cigarette smoking is the leading preventable cause of death. Unfortunately, the majority of smokers who attempt to quit smoking relapse within weeks. Abnormal dorsal anterior cingulate cortex (dACC) function may contribute to tobacco smoking relapse vulnerability. Growing evidence suggests that glutamate neurotransmission is involved in mediating nicotine dependence. We hypothesized that prior to a cessation attempt, dACC glutamate levels would be lower in relapse vulnerable smokers. Methods: Proton magnetic resonance spectra (MRS) were obtained from dACC and a control region, the parieto-occipital cortex (POC), using two-dimensional J-resolved MRS at 4 T and analyzed using LCModel. Nine nicotine-dependent women were scanned prior to making a quit attempt. Subjects then were divided into two groups; those able to maintain subsequent abstinence aided by nicotine replacement therapy (NRT) and those who slipped while on NRT (smoked any part of a cigarette after attaining at least 24 h of abstinence). Results: Slip subjects exhibited significantly reduced dACC MRS glutamate (Glu/Cr) levels (p<0.03) compared to abstinent subjects. This effect was not observed in the POC control region. Conclusions: Our preliminary findings suggest that dACC Glu levels as measured with MRS may help identify and/or be a biomarker for relapse vulnerable smokers. Future research following up on these findings may help clarify the role of dACC Glu in smoking dependence that may lead to new treatment strategies.

McGinty JF; Mendelson JE. Is brain-derived neurotrophic factor a selective biomarker that predicts cocaine relapse outcomes? (editorial). Biological Psychiatry 70(8): 700-701, 2011. (9 refs.)

Mendelson J; Baggott MJ; Flower K; Galloway G. Developing biomarkers for methamphetamine addiction. Current Neuropharmacology 9(1): 100-103, 2011. (29 refs.)

There are an estimated 11.7 million methamphetamine (MA) abusers in the United States and epidemics of MA addiction are occurring worldwide. In our human laboratory and outpatient clinical trials we use innovative methods to quantify the severity of MA addiction and test biomarkers that may predict response to therapy or risk of relapse. One potential biomarker of addiction is the quantity of abused drug intake. Qualitative urinalysis is used in clinical trials and during treatment but provides only a binary outcome measure of abuse. Using non-pharmacologic doses of deuterium labeled l-MA we have developed a continuous quantitative measure to estimate the bioavailable amount of MA addicts ingest. Brain Derived Neurotrophic Factor is a neurotrophin that encourages growth and differentiation of new neurons and synapses. Low BDNF levels are seen in many addictive disorders and BDNF is elevated in recovering MA addicts, suggesting BDNF may be a marker of MA addiction. We are investigating the effects of controlled doses of MA on BDNF levels and gene regulation and measuring BDNF in our clinical trials. We believe both patients and clinical researches will benefit from the addition of new, objective and quantifiable outcome measures that reflect disease severity and recovery from addiction.

Miller EI; Norris HRK; Rollins DE; Tiffany ST; Moore CM; Vincent MJ et al. Identification and quantification of nicotine biomarkers in human oral fluid from individuals receiving low-dose transdermal nicotine: A preliminary study. Journal of Analytical Toxicology 34(7): 357-366, 2010. (39 refs.)

The objective of this preliminary study was to identify and quantify potential nicotine (NIC) biomarkers in post-exposure oral fluid samples collected from 10 NIC-abstinent human participants administered 7 mg transdermal NIC using liquid chromatography-tandem mass spectrometry (LC-MS-MS). Oral fluid samples were collected prior to NIC patch application and at 0.5 and 0.75 h after patch removal using the Quantisal(tm) oral fluid collection device. The validated LC-MS-MS analyte panel included nicotine-N?-D-glucuronide, cotinine-N-oxide, trans-3-hydroxycotinine, norcotinine, trans-nicotine-1?-N-oxide, cotinine (COT), nornicotine, NIC, anatabine, anabasine, and cotinine-N-?-D-glucuronide. Analytes and corresponding deuterated internal standards were extracted by solid-phase extraction. NIC and COT concentrations were quantifiable in oral fluid samples collected from 6 of the 10 participants 0.5 h after patch removal and in oral fluid samples collected from 7 of the 10 participants 0.75 h after patch removal. Based on the mean NIC and COT concentrations in oral fluid and plasma for the participants with both quantifiable NIC and COT at the 0.5 and 0.75 h collection times, the oral fluid-plasma ratio was 6.4 for NIC and 3.3 for COT. An ELISA procedure was also validated and successfully applied as a screening tool for these oral fluid samples in conjunction with LC-MS-MS confirmation. An ELISA cut-off concentration of 5.0 ng/mL provided excellent sensitivity for discrimination of COT-positive post-exposure oral fluid samples collected after low-level transdermal NIC exposure and oral fluid samples collected prior to patch application.

Miranda RC; Pietrzykowski AZ; Tang YM; Sathyan P; Mayfield D; Keshavarzian A. MicroRNAs: Master regulators of ethanol abuse and toxicity? (review). Alcoholism: Clinical and Experimental Research 34(4): 575-587, 2010. (119 refs.)

Ethanol exerts complex effects on human physiology and health. Ethanol is not only addictive, but it is also a fetal teratogen, an adult neurotoxin, and an etiologic agent in hepatic and cardiovascular disease, inflammation, bone loss, and fracture susceptibility. A large number of genes and signaling mechanisms have been implicated in ethanol's deleterious effects leading to the suggestion that ethanol is a "dirty drug." An important question is, are there cellular "master-switches" that can explain these pleiotropic effects of ethanol? MicroRNAs (miRNAs) have been recently identified as master regulators of the cellular transcriptome and proteome. miRNAs play an increasingly appreciated and crucial role in shaping the differentiation and function of tissues and organs in both health and disease. This critical review discusses new evidence showing that ethanol-sensitive miRNAs are indeed regulatory master-switches. More specifically, miRNAs control the development of tolerance, a crucial component of ethanol addiction. Other drugs of abuse also target some ethanol-sensitive miRNAs suggesting that common biochemical mechanisms underlie addiction. This review also discusses evidence that miRNAs mediate several ethanol pathologies, including disruption of neural stem cell proliferation and differentiation in the exposed fetus, gut leakiness that contributes to endotoxemia and alcoholic liver disease, and possibly also hepatocellular carcinomas and other gastrointestinal cancers. Finally, this review provides a perspective on emerging investigations into potential roles of miRNAs as mediators of ethanol's effects on inflammation and fracture healing, as well as the potential for miRNAs as diagnostic biomarkers and as targets for therapeutic interventions for alcohol-related disorders.

Munafo MR; Johnstone EC; Walther D; Uhl GR; Murphy MFG; Aveyard P. CHRNA3 rs1051730 genotype and short-term smoking cessation. Nicotine & Tobacco Research 13(10): 982-988, 2011. (35 refs.)

Introduction: The rs1051730 genetic variant within the CHRNA5-A3-B4 gene cluster is associated with heaviness of smoking and has recently been reported to be associated with likelihood of stopping smoking. We investigated the potential association of rs1051730 genotype with reduced likelihood of smoking cessation in 2 cohorts of treatment-seeking smokers in primary care in the United Kingdom. Methods: Data were drawn from 2 clinical trials on which DNA was available. One sample was a randomized placebo-controlled trial of nicotine transdermal patch and the other sample an open-label trial where all participants received nicotine transdermal patch. Smoking status was biochemically verified. Logistic regression was used to assess evidence for association in each sample, and data were combined within a meta-analysis. Results: There was evidence of association of rs1051730 genotype with short-term (4-week) cessation in our open-label trial sample but not our placebo-controlled trial sample. When combined in a meta-analysis, this effect remained. There was no evidence of association at later follow-up intervals. Adjustment for cigarette consumption and tobacco dependence did not alter these results substantially. Conclusions: Our data, taken together with previous recent studies, provide some support for a weak association between this variant and short-term smoking cessation in treatment-seeking smokers, which does not seem to operate only among those receiving nicotine replacement therapy. Moreover, the rs1051730 variant may not merely operate as a marker for dependence or heaviness of smoking.

Niemela O; Alatalo P. Biomarkers of alcohol consumption and related liver disease. (review). Scandinavian Journal of Clinical & Laboratory Investigation 70(5): 305-312, 2010. (72 refs.)

Alcohol abuse is a major cause of abnormal liver function throughout the world. While measurements of liver enzyme activities (GGT, ALT, AST) are important screening tools for detecting liver disease, due to lack of ethanol-specificity and inconsistencies regarding the definitions of significant alcohol consumption, several other blood tests are usually needed to exclude competing and co-existing causes of abnormal liver function. Information on the specific role of ethanol consumption behind hepatotoxicity may be obtained through measurements of blood ethanol and its specific metabolites (ethyl glucuronide, phosphatidylethanol, protein-acetaldehyde condensates and associated autoimmune responses). Recent studies have indicated that being overweight is another increasingly common cause of abnormal liver enzyme levels and adiposity may also increase the impact of ethanol consumption on liver pathology. Interestingly, increased liver enzyme activities in circulation may reflect not only hepatic function but can also serve as indicators of general health and the status of oxidative stress in vivo. ALT and GGT activities predict insulin resistance, metabolic syndrome, mortality from coronary heart diseases and even mortality from all causes. If the upper reference limits for liver enzyme activities were defined based on the data obtained from normal weight abstainers, the clinical value of liver enzyme measurements as screening tools and in patient follow-up could be significantly improved.

Papacosta E; Nassis GP. Saliva as a tool for monitoring steroid, peptide and immune markers in sport and exercise science. (review). Journal of Science and Medicine In Sport 14(5): 424-434, 2011. (128 refs.)

Objectives: This paper discusses the use of saliva analysis as a tool for monitoring steroid, peptide, and immune markers of sports training. Design: Salivary gland physiology, regarding the regulation and stimulation of saliva secretion, as well as methodological issues including saliva collection, storage and analysis are addressed in this paper. The effects of exercise on saliva composition are then considered. Method: Exercise elicits changes in salivary levels of steroid hormones, immunoglobulins, antimicrobial proteins and enzymes. Cortisol, testosterone and dehydroepiandrosterone can be assessed in saliva, providing a non-invasive option to assess the catabolic and anabolic effects of exercise. Validation studies using blood and salivary measures of steroid hormones are addressed in this paper. Effects of acute exercise and training on salivary immunoglobulins (SIgA, SIgM, SIgG) and salivary antimicrobial proteins, including a-amylase, lysozyme and lactoferrin, are also discussed. Results: Analysis of cortisol and testosterone in saliva may help detect the onset of non-functional overreaching and subsequently may help to prevent the development of overtraining syndrome. Assessment of salivary immunoglobulins and antimicrobial proteins has been shown to successfully represent the effects of exercise on mucosal immunity. Increases in SIgA and antimicrobial proteins concentration and/or secretion rate are associated with acute exercise whereas conversely, decreases have been reported in athletes over a training season leaving the athlete susceptible for upper respiratory tract infections. Conclusions: The measurement of physiological biomarkers in whole saliva can provide a significant tool for assessing the immunological and endocrinological status associated with exercise and training.

Plebani JG; Tirado CF; Pettinati HM; Kampman KM; Volpicelli JR; Oslin DW. Combined effects of alcohol and hepatitis C: A secondary analysis of alcohol use biomarkers and high-risk behaviors from two medication trials for alcohol dependence. Addictive Behaviors 35(2): 123-128, 2010. (39 refs.)

Objectives: The goal of this secondary analysis was to examine the combined effects of HCV infection and recent alcohol use on baseline biologic markers of alcohol consumption in two outpatient medication trials for alcohol dependence. In addition. the relationship between Hepatitis C virus (HCV) infection and behavioral risk factors for HCV infection in these clinical populations were examined. Methods: Data (n=345) from two randomized, placebo-controlled trials of naltrexone and psychosocial treatment for alcohol dependence (Study 1, n=212) and comorbid alcohol and cocaine dependence (Study 11, n=133) were used to examine baseline measures of HCV risk behaviors (injection drug use, needle sharing), and biomarkers of alcohol use (AST, ALT, GGT and CDT) were compared by HCV serostatus first within each study and then across studies, Results: Although groups had differing sociodemographic profiles (as indicated by race, marital status, level of education) Subjects in Study I exhibited no statistically significant differences from the Study 11 cohort in HCV prevalence (12.7 vs. 20.0%. p=0.07), lifetime history of injection drug use (13.8 vs. 22.0%, p=0.74), lifetime history of needle sharing (9.1 vs. 18.0%, p=0.62). As such, the data from both studies were analyzed together. Regardless of drinking status, HCV infection was significantly associated with an upward shift in the baseline level of ALT, AST, and GGT (p<0.006 for all measures) and a downward shift in baseline CDT (p=0.002). When using standard laboratory cutoff values to determine clinically significant elevations, HCV seropositivity was significantly associated with elevations in ALT, AST, GGT (p <0.001), and with decreases in CDT (p=.002). Conclusions: These data emphasize the importance of evaluating HCV infection and HCV risk behaviors at intake in medication trials for alcohol dependence and also raise questions regarding the use of cutoff scores for ALT, AST, GGT and CDT levels as biologic markers of alcohol use in subjects when HCV status is unknown.

Portman M; Penttila A; Haukka J; Eriksson P; Alho H; Kuoppasalmi K. Predicting DUI recidivism of male drunken driving: A prospective study of the impact of alcohol markers and previous drunken driving. Drug and Alcohol Dependence 106(2): 186-192, 2010. (51 refs.)

The aim of the present study was to determine whether the alcohol biomarkers CDT, GGT, the biomarker gamma-CDT index and previous drunken driving contributed significantly to the prediction of DUI recidivism. The subjects consisted of two different samples of drivers, viz. drivers who were found to have a positive breath alcohol concentration during random breath testing surveys (n = 237), and drunken drivers who were apprehended during ordinary police work (n = 193). The drunken driving events were monitored using a data-base both retrospectively and prospectively. It was found that the biomarker index, gamma-CDT, emerged as a notable predictor of recidivism in the group of random breath tested drivers. Measurement of gamma-CDT and its impact on DUI recidivism has not to our knowledge been applied to random breath tested drivers before. The apprehended drunken drivers, on the other hand, did not show a significant relationship between gamma-CDT and DUI recidivism. However, in both groups of drivers it was found that a previous conviction for drunken driving strongly predicted DUI recidivism. More attention should be paid by both physicians and the police to the high risk of recidivism among those convicted of drunken driving.

Reid MJ; Langford KH; Morland J; Thomas KV. Analysis and interpretation of specific ethanol metabolites, ethyl sulfate, and ethyl glucuronide in sewage effluent for the quantitative measurement of regional alcohol consumption. Alcoholism: Clinical and Experimental Research 35(9): 1593-1599, 2011. (25 refs.)

Background: The quantitative measurement of urinary metabolites in sewage streams and the subsequent estimation of consumption rates of the parent compounds have previously been demonstrated for pharmaceuticals and narcotics. Ethyl sulfate and ethyl glucuronide are excreted in urine following the ingestion of alcohol, and are useful biomarkers for the identification of acute alcohol consumption. This study reports a novel ion-exchange-mediated chromatographic method for the quantitative measurement of ethyl sulfate and ethyl glucuronide in sewage effluent, and presents a novel calculation method for the purposes of relating the resulting sewage concentrations with rates of alcohol consumption in the region. Methods: A total of 100 sewage samples covering a 25-day period were collected from a treatment plant servicing approximately 500,000 people, and analyzed for levels of ethyl sulfate and ethyl glucuronide. The resulting data were then used to estimate combined alcohol consumption rates for the region, and the results were compared with alcohol related sales statistics for the same region. Results: Ethyl glucuronide was found to be unstable in sewage effluent. Ethyl sulfate was stable and measurable in all samples at concentrations ranging from 16 to 246 nM. The highest concentrations of the alcohol biomarker were observed during weekend periods. Sixty one percent of the total mass of ethyl sulfate in sewage effluent corresponds to alcohol consumption on Friday and Saturday. Sales statistics for alcohol show that consumption in the region is approximately 6,750 kg/d. The quantity of ethyl sulfate passing through the sewage system is consistent with consumption of 4,900 to 7,800 kg/d. Conclusions: Sewage epidemiology assessments of ethyl sulfate can provide accurate estimates of community alcohol consumption, and detailed examination of the kinetics of this biomarker in sewage streams can also identify time-dependent trends in alcohol consumption patterns.

Rendu F; Peoc'h K; Berlin I; Thomas D; Launay JM. Smoking related diseases: The central role of monoamine oxidase. (review). International Journal of Environmental Research and Public Health 8(1): 136-147, 2011. (49 refs.)

Smoking is a major risk factor of morbidity and mortality. It is well established that monoamine oxidase (MAO) activity is decreased in smokers. Serotonin (5-HT), a major substrate for MAO that circulates as a reserve pool stored in platelets, is a marker of platelet activation. We recently reported that smoking durably modifies the platelet 5-HT/MAO system by inducing a demethylation of the MAO gene promoter resulting in high MAO protein concentration persisting more than ten years after quitting smoking. The present data enlarges the results to another MAO substrate, norepinephrine (NE), further confirming the central role of MAO in tobacco use-induced diseases. Thus, MAO could be a readily accessible and helpful marker in the risk evaluation of smoking-related diseases, from cardiovascular and pulmonary diseases to depression, anxiety and cancer. The present review implements the new finding of epigenetic regulation of MAO and suggests that smoking-induced MAO demethylation can be considered as a hallmark of smoking-related cancers similarly to other aberrant DNA methylations.

Sims M; Tomkins S; Judge K; Taylor G; Jarvis MJ; Gilmore A. Trends in and predictors of second-hand smoke exposure indexed by cotinine in children in England from 1996 to 2006. Addiction 105(3): 543-553, 2010. (30 refs.)

Aims: To explore trends in and predictors of second-hand smoke (SHS) exposure in children. To identify whether inequalities in SHS exposure are changing over time. Design: Repeated cross-sectional study with data from eight annual surveys conducted over an 11-year period from 1996 to 2006. Setting: England. Participants: Nationally representative samples of children aged 4-15 years living in private households. Measurements: Saliva cotinine (4-15-year-olds), current smoking status (8-15-year-olds), smoking status of parents and carers, smoking in the home, socio-demographic variables. Findings: The most important predictors of SHS exposure were modifiable factors-whether people smoke in the house on most days, whether the parents smoke and whether the children are looked after by carers who smoke. Children from more deprived households were more exposed and this remained the case even after parental smoking status has been controlled for. Exposure over time has fallen markedly among children (59% decline over 11 years in geometric mean cotinine), with the most marked decline observed in the period immediately preceding smoke-free legislation. Declines in exposure have generally been greater in children most exposed at the outset. For example, in children whose parents both smoke, median cotinine declined annually by 0.115 ng/ml compared with 0.019 ng/ml where neither parent smokes (P < 0.05). Conclusions: In the 11 years leading up to smoke-free legislation in England, the overall level of SHS exposure in children as well as absolute inequalities in exposure have been declining. Further efforts to encourage parents and carers to quit and to avoid smoking in the home would benefit child health.

Sinha R. New findings on biological factors predicting addiction relapse vulnerability. Current Psychiatry Reports 13(5): 398-405, 2011. (94 refs.)

Relapse is a highly prevalent phenomenon in addiction. This paper examines the new research on identifying biological factors that contribute to addiction relapse risk. Prospective studies examining relapse risk are reviewed, and clinical, biological, and neural factors that predict relapse risk are identified. Clinical factors, patient-related factors, and subjective and behavioral measures such as depressive symptoms, stress, and drug craving all predict future relapse risk. Among biological measures, endocrine measures such as cortisol and cortisol/corticotropin (ACTH) ratio as a measure of adrenal sensitivity and serum brain-derived neurotrophic factor were also predictive of future relapse risk. Among neural measures, brain atrophy in the medial frontal regions and hyperreactivity of the anterior cingulate during withdrawal were identified as important in drug withdrawal and relapse risk. Caveats pertaining to specific drug abuse type and phase of addiction are discussed. Finally, significant implications of these findings for clinical practice are presented, with a specific focus on determining biological markers of relapse risk that may be used to identify those individuals who are most at risk of relapse in the clinic. Such markers may then be used to assess treatment response and develop specific treatments that will normalize these neural and biological sequelae so as to significantly improve relapse outcomes.

Stefanidou M; Athanaselis S; Spiliopoulou C; Dona A; Maravelias C. Biomarkers of opiate use. (review). International Journal of Clinical Practice 64(12): 1712-1718, 2010. (59 refs.)

The interpretation of toxicological findings is critical for the thorough investigation of the use and abuse of psychoactive substances. A positive analytical result for a sample taken could usually result in criminal proceedings and a punitive outcome for the defendant whose sample was analysed. The detection of markers of illicit opiate misuse is important both in the management of substance misuse and in the postmortem identification of illicit opiate use. The aim of this study was to emphasise the role of opiate biomarkers available at the laboratory and in the clinical environment. Urine remains the biological tool of choice for qualitative detection of illicit drug use in a clinical setting, while quantitative accuracy remains strictly the domain of blood. Accurate interpretation of the screening tests within a clinical setting alongside other relevant information remains the key to the usefulness of any test. Moreover, the finding of a morphine/codeine concentration ratio in blood exceeding unity is a strong evidence that the person had used heroin, as opposed to having taken a prescription analgesic drug containing codeine.

Stephan-Blanchard E; Chardon K; Telliez F; Arnould JP; Leke A; Ammari M et al. Are benzo[a]pyrene-DNA adducts an accurate biomarker of long-term in utero exposure to smoking? Therapeutic Drug Monitoring 33(3): 329- 335, 2011. (38 refs.)

Background: Maternal smoking during pregnancy is associated with adverse perinatal outcomes. In view of concerns about under-reporting, benzo[a] pyrene (B[a]P)-DNA adducts could be used to provide information about long-term in utero exposure to smoking but have not previously been used with samples from neonates. This study aimed to verify whether B[a] P-DNA adducts could accurately assess tobacco smoke exposure during fetal life. The objectives were to correlate B[a] P-DNA adduct levels with active maternal and passive smoking and to determine the sensitivity and specificity of smoking and nonsmoking status by comparing neonatal B[a] P-DNA adduct levels with those of maternal self-reports. Materials and Methods: B[a] P-DNA adducts in neonatal buccal cell samples were determined by a competitive immunoassay. Three groups of neonates were constituted according to maternal self-reported smoking status during pregnancy: nonsmokers (n = 25; control group), <10 cigarettes per day (n = 18; S- group), or >10 cigarettes per day (n = 21; S+ group). Results: The mean B[a] P-DNA adduct level rose significantly when comparing the controls with the S- and S+ groups. Maternal active smoking had the strongest effect on B[a] P-DNA adduct levels in neonates. A crossanalysis between B[a] P-DNA adduct levels and maternal self-reported levels revealed high sensitivity and specificity. Conclusions: This preliminary study suggests that B[a] P-DNA adducts are reliable biomarkers for the screening of long-term in utero exposure to smoking and are accurate when compared with maternal self-reported levels of active smoking. Detection of B[a] P-DNA adducts in neonates could provide a useful, noninvasive tool in clinical risk assessment studies but would benefit from further confirmation with another validated biomarker.

Stewart SH; Law TL; Randall PK; Newman R. Phosphatidylethanol and alcohol consumption in reproductive age women. Alcoholism: Clinical and Experimental Research 34(3): 488-492, 2010. (24 refs.)

Background: Fetal alcohol disorders are preventable, but self-reported alcohol consumption can be misleading and impede effective treatment. Biomarkers represent an alternative method for assessing alcohol use, and this study evaluated the relationship between blood phosphatidylethanol (PEth) and alcohol use in a sample of reproductive age women. Methods: Alcohol use was estimated by validated self-report methods in 80 nonpregnant women ages 18 to 35. PEth was measured by a contracted laboratory using a liquid chromatography-tandem mass spectrometry assay. Regression methods appropriate for the distribution of PEth were used to define its relationship to alcohol consumption during the prior 2 weeks and explore the effects of drinking patterns on this association. Receiver operating characteristic analysis was used to estimate the sensitivity of PEth for various drinking levels at 95% specific cutoffs. Results: PEth had a positive linear association with grams of alcohol consumed (p < 0.001), and was detectable in 93% of subjects consuming an average of 2 or more drinks per day. The relationship between total alcohol consumption and PEth may be stronger in women with recent heavy drinking days. The relationship between drinking and PEth varied considerably between individuals, and sensitivity for a certain amount of drinking was low at a highly specific cutoff concentration. Conclusions: PEth is a highly sensitive indicator of moderate and heavy alcohol consumption in reproductive age women and may complement the use of self-report alcohol screens when additional objective markers of alcohol use are desirable. However, choosing a highly valid cutoff concentration for PEth to differentiate various levels of alcohol

Sung J; Lee K; Song YM. Heritabilities of Alcohol Use Disorders Identification Test (AUDIT) scores and alcohol biomarkers in Koreans: The KoGES (Korean Genome Epi Study) and Healthy Twin Study. Drug and Alcohol Dependence 113(2-3): 104-109, 2011. (32 refs.)

Background: Both the Alcohol Use Disorders Identification Test (AUDIT) and alcohol biomarkers are used to screen for alcohol problems. The purpose of this study was to examine the genetic and environmental contributions to the AUDIT score and alcohol biomarkers in Koreans. Methods: The study included 1678 current alcohol drinkers: 818 Korean twins and 860 their families. The Korean version of AUDIT and alcohol biomarkers, i.e., gamma glutamyltransferase (GGT), alanine aminotransferase (ALT), mean corpuscular volume (MCV), and triglycerides (TG), were studied. The analyses were conducted using variance components method to estimate heritability and common environmental effects, and bivariate analyses for genetic and environmental correlations between the AUDIT score and the biomarkers after adjustment for age, gender, interaction of age and gender, smoking status, the amount of consumed alcohol, body mass index, and education. Results: Heritabilities for the AUDIT score were 0.35 and 0.40-0.71 for biomarkers (P<0.001). The risk of alcohol problems using AUDIT score was positively associated with the levels of biomarkers (GGT, MCV, and TG) in men, while the relationship was significant only for MCV in women. Genetic or environmental correlations between the AUDIT score and some of the biomarkers (GGT and MCV) were significant in men, but not significant in women. Conclusions: We found a significant genetic contribution to the AUDIT score and the alcohol biomarkers. As there were significant genetic and environmental relationships between the AUDIT score and the alcohol biomarkers in men, future studies are warranted to identify common genes and environmental effects affecting the relationships.

Thiesen H; Hesse M. Biological markers of problem drinking in homeless patients. Addictive Behaviors 35(3): 260-262, 2010. (16 refs.)

Objective: In the search for optimal biomarkers of excessive drinking, a central limitation has been the lack of sensitivity of measures. Many patients have apparently normal values of liver markers despite a considerable alcohol intake. This study aimed to test a novel combined indicator of alcohol drinking. Material and methods: Concentrations of carbohydrate-deficient transferrin (%CDT), gamma glutamyl transferase (gamma GT), aspartate aminotransferase (ASAT), and mean corpuscular volume (MCV), together with a combined index of the %CDT and gamma GT, the c (AI), were studied in 104 homeless patients with (n = 87) or without (n = 24) problem drinking according to the Fast Alcohol Screening Test. Results: Concentrations of all markers were significantly higher in the alcoholic patients than in other homeless patients. The best agreement between liver markers and self-reported status was found between the combined %CDT and gamma GT index (kappa = 0.61, p<0.001, sensitivity = 63%, specificity = 94%). Conclusions: The combined Antilla Index is a relatively efficient measure of current drinking in homeless populations.

Varenbut M; Plater-Zyberk C; Worster A; Daiter J. Does low urine creatinine level indicate the presence of urine alcohol in methadone maintenance treatment patients? American Journal of Drug and Alcohol Abuse 36(4): 199-201, 2010. (19 refs.)

Objective: We sought to test the assumption that a low urine creatinine level is indicative of the presence of alcohol in the urine of patients prescribed methadone. Methods: This is a medical record review of 261,055 urine samples from approximately 6,000 patients prescribed methadone during a one-year period and for whom both urine creatinine and ethanol levels were simultaneously measured. We defined a creatinine level of less than 2.26 mmol/L as 'low' used a urine ethanol level of greater than 2.0 mmol/L as the reference standard for alcohol consumption. Results: The sensitivity and specificity of low urine creatinine as a marker for the detection of urine ethanol are 11.9% (95% CI: 11.3, 12.5%) and 96.7% (95% CI: 96.7, 96.7%), respectively. In this patient population with a low (3.6%) prevalence of alcohol in the urine, the results correspond to a positive predictive value of 11.9% (95% CI: 11.3, 12.6%) and a negative predictive value of 96.7% (95% CI: 96.7, 96.7%), respectively. Conclusions: Low urine creatinine is a poor screening test for detecting alcohol consumption among patients on methadone. However, a normal creatinine level has a 96.7% probability of no alcohol urine present in the urine.

Vollstadt-Klein S; Loeber S; Winter S; Lemenager T; von der Goltz C; Dinter C et al. Attention shift towards smoking cues relates to severity of dependence, smoking behavior and breath carbon monoxide. European Addiction Research 17(4): 217- 224, 2011. (32 refs.)

The aim of this study was to assess the severity of dependence as a factor affecting the attentional bias of smokers towards smoking-related stimuli and to clarify contradictory results of previous studies. A visual dot probe task was administered to 51 smokers and 41 nonsmokers to assess the attentional bias. Smokers were classified into a group of less severely dependent and a group of more severely dependent smokers according to the Fagerstrom Test for Nicotine Dependence, the number of cigarettes smoked per day or the CO concentration in the expired air. Nicotine craving was assessed as well. The more severely dependent smokers displayed an attentional bias towards smoking-related stimuli, while smokers with less severe nicotine dependence showed a negative attentional bias which was also observed in nonsmokers. A multiple linear regression indicated that CO concentration was the only significant predictor of attentional bias. In the total group of smokers we found a positive association between attentional bias and craving for the rewarding effects of nicotine. Future studies are warranted to further enhance our understanding of factors that affect attentional bias as appetitive responses towards smoking- related stimuli might be an important target for therapeutic interventions.

Vyssoki B; Steindl-Munda P; Ferenci P; Walter H; Hofer P; Bluml V et al. Comparison of alcohol-dependent patients at a gastroenterological and a psychiatric ward according to the Lesch Alcoholism Typology: Implications for treatment. Alcohol and Alcoholism 45(6): 534-540, 2010. (42 refs.)

Aims: To assess the clinical and biological status of alcohol-dependent patients admitted to a psychiatric or a gastroenterological ward, assessing and comparing dimensions important for prescribing treatment for withdrawal and relapse prevention. Methods: Eighty patients, alcohol-dependent according to international classification of diseases tenth revision and diagnostic and statistical manual, text revised, version IV, admitted to the Vienna General Hospital between January 2005 and November 2006, were examined, of whom 44 were admitted to the psychiatric ward and 36 to the gastroenterological ward. Dimensions of alcohol dependence were assessed using a computerized structured interview, the Lesch alcoholism typology (LAT). Biological markers and the model for end-stage liver disease (MELD) score defined the severity of alcohol-related physical disturbances. Results: As might be expected, gastroenterological patients had more advanced physical diseases than psychiatric patients, and affective disorders and suicidal tendencies were significantly commoner among the psychiatric patients. Thus, LAT Type II patients were overrepresented at the gastroenterological ward and LAT Type III patients at the psychiatric ward. Conclusion: The severity of somatic diseases and psychiatric disorders as well as the distribution of the four types according to Lesch differ between alcohol-dependent patients admitted to a psychiatric ward or a gastroenterological ward. Regarding the positive long-term outcome, different evidence-based medical treatment approaches for withdrawal and relapse prevention are needed for these patients.

Waszkiewicz N; Konarzewska B; Waszkiewicz M; Poplawska R; Szajda SD; Zalewska A et al. Biomarkers of alcohol abuse. Part I. Traditional biomarkers and their interpretation. Psychiatria Polska 44(1): 127-136, 2010. (35 refs.)

Approximately 15% of the Polish population abuse alcohol. Early detection of alcohol problems may prevent their further development and progression. The study reviews traditional biomarkers associated with alcohol abuse. The nature of biomarkers, their practical application and limitations in alcohol abuse detection, in assessment and monitoring of drinking, are reviewed. Despite the limited sensitivity and specificity in alcohol abuse detection, traditional biomarkers remain useful in alcohol abuse detection. They are widely available and relatively inexpensive, providing valuable data on complications of drinking and prognosis as well as on concurrent conditions affected by drinking.

Waszkiewicz N; Poplawska R; Konarzewska B; Szajda SD; Galinska B; Rutkowski P et al. Biomarkers of alcohol abuse. Part II. New biomarkers and their interpretation. Psychiatria Polska 44(1): 137-146, 2010. (34 refs.)

An increasing number of new biomarkers of alcohol abuse appear in the literature. The most commonly used biomarkers (5-hydroxytryptophol, fatty acid ethyl esters, ethyl glucuronide, phosphatidyl ethanol, ethyl sulphate, mitochondrial aspartate aminotransferase, carbohydrate deficient transferrin, acetaldehyde adducts, beta-hexosaminidase, and sialic acid) were described. Then other known and less known biomarkers associated with alcohol abuse were described in brief (e.g. acetaldehyde, acetate, methanol, alpha-amino-n-butyric acid, dolichol, proteomics). Their sensitivity and specificity is generally higher than that of traditional biomarkers. The time of detection in biological fluids occur from one day to few months after alcohol consumption. Hence, their usefulness in clinical practice as well as in experimental studies is increasing.

Woodward A. Commentary on Sims et al. (2010): The decline in passive smoking. (editorial). Addiction 105(3): 554-555, 2010. (12 refs.)

Wurst FM; Thon N; Yegles M; Halter C; Weinmann W; Laskowska B et al. Optimizing heroin-assisted treatment: Assessment of the contribution of direct ethanol metabolites in identifying hazardous and harmful alcohol use. Drug and Alcohol Dependence 115(1-2): 57- 61, 2011. (40 refs.)

Background: Heavy alcohol consumption may accelerate the progression of hepatitis C-related liver disease and/or limit efforts at antiviral treatment in opioid-dependent patients receiving heroin-assisted treatment (HAT). Our study aims to assess alcohol intake among HAT patients by self-reports compared to direct ethanol metabolites. Method: Fifty-four patients in HAT were recruited from the centre for HAT at the University of Basel, Switzerland. The patients completed the Alcohol Use Disorder Identification Test (AUDIT), a self-report questionnaire on past-week ethanol intake and provided samples for the determination of ethyl glucuronide (UEtG) and ethyl sulphate (UEtS) in urine and of ethyl glucuronide (HEtG) in hair. Results: Eighteen patients scored above the AUDIT cut-off levels. Twenty-six patients tested positive for UEtG and 29 for UEtS. HEtG identified ethanol intake of more than 20 g/d in 20 additional cases that did not appear in the AUDIT. Using the total score of the AUDIT, HEtG detected 14 additional cases of relevant alcohol intake. Conclusions: The findings of this study, which is the first assessing alcohol intake in HAT patients using direct ethanol metabolites and self reports, suggest the complementary use of both. Improved detection of hazardous or harmful alcohol consumption in the context of HCV and heroin dependence will allow for earlier intervention in this population. This ultimately will contribute to an improvement in quality of life of patients in HAT. Furthermore, a significant reduction of costs can be achieved through a reduction of complications caused by alcohol intake.