Search

Background: Upregulation of the endocannabinoid enzyme fatty acid amide hydrolase (FAAH) has been linked to abnormal activity in frontoamygdalar circuits, a hallmark of posttraumatic stress disorder. We tested the hypothesis that FAAH levels in the amygdala were negatively correlated with functional connectivity between the amygdala and prefrontal cortex, subserving stress and affect control., Methods: Thirty-one healthy participants completed positron emission tomography (PET) imaging with the FAAH probe [C-11]CURB, and resting-state functional MRI scans. Participants were genotyped for the FAAH polymorphism rs324420, and trait neuroticism was assessed. We calculated amygdala functional connectivity using predetermined regions of interest (including the subgenual ventromedial prefrontal cortex [sgvmPFC] and the dorsal anterior cingulate cortex [dACC]) and a seed-to-voxel approach. We conducted correlation analyses on functional connectivity, with amygdala [C-11]CURB binding as a variable of interest., Results: The strength of amygdala functional connectivity with the sgvmPFC and dACC was negatively correlated with [C-11]CURB binding in the amygdala (sgvmPFC: r = -0.38, q = 0.04; dACC: r = -0.44; q = 0.03). Findings were partly replicated using the seed-to-voxel approach, which showed a cluster in the ventromedial prefrontal cortex, including voxels in the dACC but not the sgvmPFC (cluster-level, family-wise error rate corrected p < 0.05)., Limitations: We did not replicate earlier findings of a relationship between an FAAH polymorphism (rs324420) and amygdala functional connectivity., Conclusion: Our data provide preliminary evidence that lower levels of FAAH in the amygdala relate to increased frontoamygdalar functional coupling. Our findings were consistent with the role of FAAH in regulating brain circuits that underlie fear and emotion processing in humans., Competing Interests: M. Hill has served on scientific advisory boards for Lundbeck and Sophren Therapeutics. R. Tyndale has consulted for Quinn Emanuel and Ethismos on unrelated topics. No other competing interests declared., (© 2021 Joule Inc. or its licensors.)

Background: Reduced function of fatty acid amide hydrolase, the catabolic enzyme for the endocannabinoid anandamide, can be inherited through a functional genetic polymorphism (FAAH rs324420, C385A, P129T). The minor (A) allele has been associated with reduced FAAH enzyme activity and increased risk for substance use disorders in adults. Whether this inherited difference in endocannabinoid metabolism relates to alcohol use disorder etiology and patterns of alcohol use in youth is unknown., Methods: To examine this question, heavy-drinking youth (n = 302; mean age = 19.74 ± 1.18) were genotyped for FAAH C385A. All subjects completed a comprehensive interview assessing alcohol use patterns including the Timeline Follow-back Method, Alcohol Use Disorders Identification Test (AUDIT), and Drinking Motives Questionnaire. Analyses of Covariance (ANCOVAs) were conducted to assess differences in drinking patterns and drinking motives between genotype groups, and mediation analyses investigated whether drinking motives accounted for indirect associations of genotype with alcohol use severity., Results: Youth with the FAAH minor allele (AC or AA genotype) reported significantly more drinking days (p = 0.045), significantly more frequent heavy episodic drinking (p = 0.003), and significantly higher alcohol-related problems and consumption patterns (AUDIT score p = 0.045, AUDIT-C score p = 0.02). Mediation analyses showed that the association of FAAH C385A with drinking outcomes was mediated by coping motives., Conclusions: These findings extend previous studies by suggesting that reduced endocannabinoid metabolism may be related to heavier use of alcohol in youth, prior to the onset of chronic drinking problems. Furthermore, differences in negative reinforcement-related drinking could account in part for this association., (© 2021 by the Research Society on Alcoholism.)

Background: The objective of this project is to determine the effectiveness of targeting a community with a high smoking rate with the distribution of free-of-charge nicotine patches in order to promote tobacco cessation., Methods/design: One small community with an elevated smoking rate (compared to national and provincial averages) has been identified. All households in the community will be sent a letter offering one smoker (18 years or older; 10 or more cigarettes per day) in the household a free-of-charge mailed five-week supply of nicotine patches (up to a total of 800 five-week kits will be available for distribution). Participants receiving nicotine patches will be asked to complete a six-month follow-up survey assessing tobacco cessation defined as 30-day point prevalence abstinence. In addition, attempts will be made to employ ongoing national population surveys containing cigarette smoking variables to compare changes in smoking prevalence in the target community to other communities with similar characteristics., Discussion: We will examine whether the concentrated distribution of mailed nicotine patches will result in a measurable reduction in smoking rates in the target community. If demonstrated, this would provide support for the targeted population-level distribution of an effective individual-level public health intervention., Clinical Trials Registration: NCT04534231.

Introduction: The cannabinoid CB1 receptor (CB1R) has been shown in preclinical studies to be involved in nicotine reinforcement and relapse-like behavior. The common single nucleotide polymorphism (SNP) rs2023239 may code for an alternative CB1R protein, alter CB1R expression, and be involved in nicotine dependence. To date, no study has explored the relationship between this SNP in CB1R and specific phenotypes of nicotine dependence., Methods: The current study investigated the influence of CB1R rs2023239 in nicotine reinforcement and craving in regular cigarette smokers. Current smokers (n = 104, cigarettes per day ≥ 10) were genetically grouped (C allele group vs. No C allele group) and underwent laboratory measures of nicotine reinforcement and smoking cue-elicited craving. Nicotine reinforcement was assessed using a forced choice paradigm, while a cue-reactivity procedure measured cue-elicited craving., Results: These results show that smokers with the C allele variant (CC + CT genotypes) experienced a lower nicotine reinforcement effect compared to those without the C allele (TT genotype). These results were similar in both our subjective and behavioral reinforcement measures, though the subjective effects did not withstand controlling for race. There was no difference between genotype groups with respect to cue-elicited craving, suggesting a lack of influence in cue reactivity., Conclusion: Taken together, these results suggest that the variation in the CB1R (i.e., rs2023239 SNP) may play a larger role in nicotine reinforcement compared to cue reactivity. This work provides impetus to further understand the physiological mechanisms that explain how CB1Rs influence nicotine dependence phenotypes., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

We have recently shown that levels of fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide, are lower in the brains of adult cannabis users (CUs) (34 ± 11 years of age), tested during early abstinence. Here, we examine replication of the lower FAAH levels in a separate, younger cohort (23 ± 5 years of age). Eighteen healthy volunteers (HVs) and fourteen CUs underwent a positron emission tomography scan using the FAAH radioligand [ 11 C]CURB. Regional [ 11 C]CURB binding was calculated using an irreversible two-tissue compartment model with a metabolite-corrected arterial plasma input function. The FAAH C385A genetic polymorphism (rs324420) was included as a covariate. All CUs underwent a urine screen to confirm recent cannabis use and had serum cannabinoids measured. One CU screened negative for cannabinoids via serum and was removed from analysis. All HVs reported less than five lifetime cannabis exposures more than a month prior to study initiation. There was a significant effect of group (F 1,26 = 4.31; P = .048) when two A/A (rs324420) HVs were removed from analysis to match the genotype of the CU group (n = 16 HVs, n = 13 CUs). Overall, [ 11 C]CURB λk 3 was 12% lower in CU compared with HV. Exploratory correlations showed that lower brain [ 11 C]CURB binding was related to greater use of cannabis throughout the past year. We confirmed our previous report and extended these findings by detecting lower [ 11 C]CURB binding in a younger cohort with less cumulative cannabis exposure., (© 2020 Society for the Study of Addiction.)

CYP2A enzymes metabolically inactivate nicotine and activate tobacco-derived procarcinogens [e.g., 4-[methylnitrosamino]-1-(3-pyridyl)-1-butanone]. Smoking decreases nicotine clearance, and chronic nicotine reduces hepatic CYP2A activity. However, little is known about the impact of smoking or nicotine on the expression of CYP2A in the lung. We investigated 1) the levels of human lung CYP2A mRNA in smokers versus nonsmokers and 2) the impact of daily nicotine treatment on lung CYP2A protein levels in African green monkeys (AGMs). Lung CYP2A13, CYP2A6, and CYP2A7 (and CYP1A2) mRNA levels in smokers and nonsmokers were assessed in Gene Expression Omnibus data sets (GSE30063, GSE108134, and GSE11784). The impact of chronic, twice-daily, subcutaneous nicotine at two doses (0.3 and 0.5 mg/kg) versus vehicle on lung CYP2A protein levels was assessed. The impact of ethanol self-administration was also investigated, with and without nicotine treatment. Smokers versus nonsmokers (from GSE30063 and GSE108134) had lower (1.04- to 1.12-fold) levels of lung CYP2A13, CYP2A6, and CYP2A7 (and higher CYP1A2) mRNA. Both doses of nicotine tested decreased AGM lung CYP2A protein (3- to 7-fold). Ethanol self-administration had no effect on AGM lung CYP2A protein, and there was no interaction between ethanol and nicotine. Our results suggest that smoking was associated with a reduction in human lung CYP2A13, CYP2A6, and CYP2A7 mRNA, consistent with the role of nicotine treatment in reducing AGM lung CYP2A protein. This regulation by smoking/nicotine will increase interindividual variation in lung CYP2A levels, which may impact the localized metabolism of inhaled drugs and tobacco smoke procarcinogens. SIGNIFICANCE STATEMENT: CYP2A13 and CYP2A6 are expressed in the lung and may contribute to local procarcinogen activation. Smokers had lower lung CYP2A mRNA levels compared with nonsmokers. Lung CYP2A protein expression was decreased by systemic treatment with nicotine. Decreased lung CYP2A expression may alter smoking-related lung cancer risk and tissue damage from other inhaled toxins. This novel regulatory impact of nicotine, including nicotine found in smoking-cessation nicotine-replacement therapies, may have potential benefits on smoking-related lung cancer risk., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: The smoking behavior of American Indians (AI) differs from that of non-Hispanic whites (NHW). Typically light smokers, cessation interventions in AIs are generally less effective. To develop more effective cessation programs for AIs, clinicians, researchers, and public health workers need a better understanding of the genetic factors involved in their smoking behavior. Our aim was to assess whether SNPs associated with smoking behavior in NHWs are also associated with smoking in AIs., Methods: We collected questionnaire data on smoking behaviors and analyzed blood and saliva samples from two Tribal populations with dramatically different cultures and smoking prevalence, one in the Northern Plains ( n = 323) and the other in the Southwest ( n = 176). A total of 384 SNPs were genotyped using an Illumina custom GoldenGate platform. Samples were also assessed for cotinine and 3-hydroxycotinine as markers of nicotine intake and nicotine metabolite ratio., Results: Among 499 participants, we identified, in the Northern Plains sample only, a variant of the gamma-aminobutyric acid receptor subunit alpha-2 ( GABRA2 ) (rs2119767) on chromosome 4p that was associated with many of the intake biomarkers of smoking we examined, suggesting a role for this gene in modifying smoking behavior in this population. We also identified three SNPs, in the Southwest sample only, as significant correlates of only cigarettes per day: rs4274224, rs4245147 (both dopamine receptor D2 gene), and rs1386493 (tryptophan hydroxylase 2 gene)., Conclusions: The contribution of many genes known to underlie smoking behaviors in NHWs may differ in AIs., Impact: Once validated, these variants could be useful in developing more effective cessation strategies., (©2020 American Association for Cancer Research.)

We examined whether elucidating underpinning smoking motivation and related pharmacological processes enhances understanding of nicotine dependence among smokers from vulnerable populations. Data were obtained between Oct, 2016 and Sept, 2019 from 745 adult smokers with co-morbid psychiatric conditions or socioeconomic disadvantage at University of Vermont, Brown University, Johns Hopkins University. Smoking motivation was assessed using the Cigarette Purchase Task (CPT), a behavioral-economic task that models the relative reinforcing value of smoking under varying monetary constraint. Dependence severity was measured using the Heaviness of Smoking Index (HSI), Fagerström Test for Nicotine Dependence total scores (FTND), and FTND total scores minus items 1 and 4 (FTND 2,3,5,6 ). We also assessed associations between dependence severity and smoking motivation with nicotine levels and metabolism rate. Principal Component Analysis was used to examine the latent structure of the conventional five CPT indices; bivariate and multivariable modeling was used to test associations. Factor analysis resulted in a two-factor solution, Amplitude (demand unconstrained by price) and Persistence (price sensitivity). CPT latent factors were associated with each dependence-severity measure (ps ≤ 0.0001), with associations stronger for Amplitude than Persistence across each, especially HSI which was exclusively associated with Amplitude . Amplitude and each dependence measure were associated with nicotine intake (ps ≤ 0.0002); Persistence was not (p = .19). Demand Amplitude more than Persistence appears key to understanding individual differences in dependence severity. Regarding potential application, the results suggest a need for interventions that more effectively target demand Amplitude to make greater headway in reducing smoking in vulnerable populations. Trial Registration:clinicaltrials.gov identifiers: NCT02232737, NCT02250664, NCT02250534., (Copyright © 2020 Elsevier Inc. All rights reserved.)

CYP2D6 metabolically inactivates several neurotoxins, including beta-carbolines, which are implicated in neurodegenerative diseases. Variation in CYP2D6 within the brain may alter local inactivation of neurotoxic beta-carbolines, thereby influencing neurotoxicity. The beta-carboline harmine, which induces hypothermia and tremor, is metabolized by CYP2D6 to the non-hypothermic/non-tremorgenic harmol. Transgenic mice (TG), expressing human CYP2D6 in addition to their endogenous mouse CYP2D, experience less harmine-induced hypothermia and tremor compared with wild-type mice (WT). We first sought to elucidate the role of CYP2D in general within the brain in harmine-induced hypothermia and tremor severity. A 4-h intracerebroventricular (ICV) pretreatment with the CYP2D inhibitor propranolol increased harmine-induced hypothermia and tremor in TG and increased harmine-induced hypothermia in WT. We next sought to specifically demonstrate that human CYP2D6 expressed in TG brain altered harmine response severity. A 24-h ICV propranolol pretreatment, which selectively and irreversibly inhibits human CYP2D6 in TG brain, increased harmine-induced hypothermia. This 24-h pretreatment had no impact on harmine response in WT, as propranolol is not an irreversible inhibitor of mouse CYP2D in the brain, thus confirming no off-target effects of ICV propranolol pretreatment. Human CYP2D6 activity in TG brain was sufficient in vivo to mitigate harmine-induced neurotoxicity. These findings suggest that human CYP2D6 in the brain is protective against beta-carboline-induced neurotoxicity and that the extensive interindividual variability in CYP2D6 expression in human brain may contribute to variation in susceptibility to certain neurotoxin-associated neurodegenerative disorders.

Background: The brain's endocannabinoid system, the primary target of cannabis, has been implicated in psychosis. The endocannabinoid anandamide is elevated in cerebrospinal fluid of patients with schizophrenia. Fatty acid amide hydrolase (FAAH) controls brain anandamide levels; however, it is unknown if FAAH is altered in vivo in psychosis or related to positive psychotic symptoms., Methods: Twenty-seven patients with schizophrenia spectrum disorders and 36 healthy control subjects completed high-resolution positron emission tomography scans with the novel FAAH radioligand [ 11 C]CURB and structural magnetic resonance imaging. Data were analyzed using the validated irreversible 2-tissue compartment model with a metabolite-corrected arterial input function., Results: FAAH did not differ significantly between patients with psychotic disorders and healthy control subjects (F 1,62.85  = 0.48, p = .49). In contrast, lower FAAH predicted greater positive psychotic symptom severity, with the strongest effect observed for the positive symptom dimension, which includes suspiciousness, delusions, unusual thought content, and hallucinations (F 1,26.69  = 12.42, p = .002; Cohen's f = 0.42, large effect). Shorter duration of illness (F 1,26.95  = 13.78, p = .001; Cohen's f = 0.39, medium to large effect) and duration of untreated psychosis predicted lower FAAH (F 1,26.95  = 6.03, p = .021, Cohen's f = 0.27, medium effect). These results were not explained by past cannabis exposure or current intake of antipsychotic medications. FAAH exhibited marked differences across brain regions (F 7,112.62  = 175.85, p < 1 × 10 -56 ; Cohen's f > 1). Overall, FAAH was higher in female subjects than in male subjects (F 1,62.84  = 10.05, p = .002; Cohen's f = 0.37)., Conclusions: This first study of brain FAAH in psychosis indicates that FAAH may represent a biomarker of disease state of potential utility for clinical studies targeting psychotic symptoms or as a novel target for interventions to treat psychotic symptoms., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Cytochrome P450 2D (CYP2D) mediates the activation and inactivation of several classes of psychoactive drugs, including opioids, which can alter drug response. Tramadol is a synthetic opioid with analgesic activity of its own as well as being metabolically activated by CYP2D to O-desmethyltramadol (ODMST) an opioid receptor agonist. We investigated the impact of brain CYP2D metabolism on central tramadol and ODSMT levels, and resulting analgesic response after oral tramadol administration in rats. CYP2D inhibitors propranolol and propafenone were administered intracerebroventricularly prior to oral tramadol administration and analgesia was measured by tail-flick latency. Drug levels of tramadol and its metabolites, ODSMT and N-desmethyltramadol, were assessed in plasma and in brain by microdialysis using LC-ESI-MS/MS. Inhibiting brain CYP2D with propafenone pretreatment increased analgesia after oral tramadol administration (ANOVA p = 0.02), resulting in a 1.5-fold increase in area under the analgesia-time curve (AUC 0-60 , p < 0.01). This effect was associated with changes in the brain levels of tramadol and its metabolites consistent with brain CYP2D inhibition. In conclusion, under oral tramadol dosing pretreatment with a central administration of the CYP2D inhibitor propafenone increased analgesia (without altering plasma drug or metabolite levels), indicating that tramadol itself (and activity of CYP2D within the brain) contributed to analgesia., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The prevalence of "vaping" has recently seen significant increases in North America, especially in adolescents. However, the behavioral correlates of vaping are largely unexplored. The uptake of existing technologies meant for rodent vapor inhalation remains limited because of a lack of affordability and versatility (ability to be used with a variety of vaporizers). The OpenVape (OV) offers an open-source, low-cost solution that can be used in a variety of research contexts. Here, we present a specific use case, combining the OV apparatus with JUUL e-cigarettes. This apparatus consists of Arduino-operated vacuum pumps that deliver vapor directly from e-cigarettes to exposure chambers. The OV is easy to build and customize for any type of vaporizer (e.g., nicotine pod or tank; cannabis flower or concentrates). To test the OV, we performed biochemical verification and behavioral studies. The behavioral test (conditioned place preference, CPP) was conducted using adolescent and adult animals to assess developmental differences in the rewarding effects of nicotine vapor, as previously observed with injected nicotine. These findings demonstrate that even after brief exposures to nicotine vapor, pharmacologically relevant nicotine and cotinine levels could be detected in plasma, and significant CPP was observed, especially in adolescent rats which showed preference at shorter puff delivery durations (lower nicotine doses) compared with adults. Together, these findings suggest that OV provides an affordable, open-source option for preclinical behavioral research into the effects of vaping., (Copyright © 2020 Frie et al.)

Introduction: Pregnant women exposed chronically to opioids smoked more cigarettes per day (CPD) and had a higher nicotine metabolite ratio (NMR), 3-hydroxycotinine/cotinine, a biomarker of nicotine metabolism and clearance, than those not receiving opioids. We examined CPD and NMR in a group of pregnant smokers, a quarter of whom were receiving opioid agonist therapy (OAT)., Aims and Methods: Pregnant smokers recruited to participate in a placebo-controlled trial of bupropion for smoking cessation provided a blood sample for measurement of NMR., Results: Half (52.4%) of the 124 women with NMR data were African American. OAT-treated women (n = 34, 27.4%; 27 receiving methadone and 7 buprenorphine) were more likely to be white (79% vs. 30%, p < .001) and to have a lower mean PHQ-9 total score (2.91 [SD = 2.83] vs. 4.83 [SD = 3.82], p = .007). OAT-treated women reported smoking more CPD (9.50 [SD = 5.26] vs. 7.20 [SD = 3.65], p = .005) and had higher NMR (0.78 [SD = 0.36] vs. 0.56 [SD = 0.25], p = .001) than the non-OAT-treated group. In a linear regression analysis adjusting for race, depression severity, and CPD, NMR was greater in the OAT group (p = .025), among whom the daily methadone-equivalent dosage correlated with NMR (Spearman's ρ = 0.49, p = .003)., Conclusions: Consistent with the findings of Oncken et al. (2019), we found that OAT smokers smoked more and had higher NMR than non-OAT smokers. As higher NMR is associated with a reduced likelihood of smoking cessation, the effects on NMR of both pregnancy and OAT could contribute to a lower smoking cessation rate in pregnant smokers receiving chronic opioid therapy., Implications: We replicated the finding that the NMR is significantly greater among pregnant smokers receiving OAT than those not receiving this treatment for opioid use disorder. Furthermore, we found that the dosage of the OAT was significantly associated with the NMR level. These findings may contribute to a poorer response to smoking cessation treatment in pregnant women treated with OAT, particularly those receiving high-dose therapy, and raise the question of whether novel approaches are needed to treat smoking in this subgroup of pregnant smokers., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.)

Smoking is a major contributor to lung cancer and chronic obstructive pulmonary disease (COPD). Two of the strongest genetic associations of smoking-related phenotypes are the chromosomal regions 15q25.1, encompassing the nicotinic acetylcholine receptor subunit genes CHRNA5-CHRNA3-CHRNB4, and 19q13.2, encompassing the nicotine metabolizing gene CYP2A6. In this study, we examined genetic relations between cigarettes smoked per day, smoking cessation, lung cancer, and COPD. Data consisted of genome-wide association study summary results. Genetic correlations were estimated using linkage disequilibrium score regression software. For each pair of outcomes, z-score-z-score (ZZ) plots were generated. Overall, heavier smoking and decreased smoking cessation showed positive genetic associations with increased lung cancer and COPD risk. The chromosomal region 19q13.2, however, showed a different correlational pattern. For example, the effect allele-C of the sentinel SNP (rs56113850) within CYP2A6 was associated with an increased risk of heavier smoking (z-score = 19.2; p = 1.10 × 10 -81 ), lung cancer (z-score = 8.91; p = 5.02 × 10 -19 ), and COPD (z-score = 4.04; p = 5.40 × 10 -5 ). Surprisingly, this allele-C (rs56113850) was associated with increased smoking cessation (z-score = -8.17; p = 2.52 × 10 -26 ). This inverse relationship highlights the need for additional investigation to determine how CYP2A6 variation could increase smoking cessation while also increasing the risk of lung cancer and COPD likely through increased cigarettes smoked per day., (© 2020 Wiley Periodicals LLC.)

Dopamine is a catecholamine neurotransmitter that degrades rapidly in aqueous solutions; hence, its analysis following brain microdialysis is challenging. The aim of the current study was to develop and validate a new microdialysis coupled LC-MS/MS system with improved accuracy, precision, simplicity and turnaround time for dopamine, serotonin, methamphetamine, amphetamine, 4-hydroxymethamphetamine and 4-hydroxyamphetamine analysis in the brain. Dopamine degradation was studied with different stabilizing agents under different storage conditions. The modified microdialysis system was tested in vitro, and was optimized for best probe recovery, assessed by %gain. LC-MS/MS assay was developed and validated for the targeted compounds. Stabilizing agents (ascorbic acid, EDTA and acetic acid) as well as internal and cold standards were added on-line to the dialysate flow. Assay linearity range was 0.01-100 ng/mL, precision and accuracy passed criteria, and LOQ and LLOQ were 0.2 and 1.0 pg, respectively. The new microdialysis coupled LC-MS/MS system was used in Wistar rats striatum after 4 mg/kg subcutaneous methamphetamine. Methamphetamine rapidly distributed to rat striatum reaching an average ~200 ng/mL maximum, ~82.5 min post-dose. Amphetamine, followed by 4-hydroxymethamphetamine, was the most abundant metabolite. Dopamine was released following methamphetamine injection, while serotonin was not altered. In conclusion, we proposed and tested an innovative and simplified solution to improve stability, accuracy and turnover time to monitor unstable molecules, such as dopamine, by microdialysis., Competing Interests: Declaration of Competing Interest R.F.T. has consulted for Quinn Emanuel and Ethismos on unrelated topics. All other authors declare no competing interests., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: By improving our understanding of the neurobiological mechanisms underlying addiction, neuroimaging research is helping to identify new targets for personalized treatment interventions. When trying to quit, smokers with larger electrophysiological responses to cigarette-related, compared with pleasant, stimuli ("C > P") are more likely to relapse than smokers with the opposite brain reactivity profile ("P > C")., Aim and Method: The goal was to (1) build a classification algorithm to identify smokers characterized by P > C or C > P neuroaffective profiles and (2) validate the algorithm's classification outcomes in an independent data set where we assessed both smokers' electrophysiological responses at baseline and smoking abstinence during a quit attempt. We built the classification algorithm applying discriminant function analysis on the event-related potentials evoked by emotional images in 180 smokers., Results: The predictive validity of the classifier showed promise in an independent data set that included new data from 177 smokers interested in quitting; the algorithm classified 111 smokers as P > C and 66 as C > P. The overall abstinence rate was low; 15 individuals (8.5% of the sample) achieved CO-verified 12-month abstinence. Although individuals classified as P > C were nearly 2.5 times more likely to be abstinent than smokers classified as C > P (12 vs. 3, or 11% vs. 4.5%), this result was nonsignificant, preliminary, and in need of confirmation in larger trials., Conclusion: These results suggest that psychophysiological techniques have the potential to advance our knowledge of the neurobiological underpinnings of nicotine addiction and improve clinical applications. However, larger sample sizes are necessary to reliably assess the predictive ability of our algorithm., Implications: We assessed the clinical relevance of a neuroimaging-based classification algorithm on an independent sample of smokers enrolled in a smoking cessation trial and found those with the tendency to attribute more relevance to rewards than cues were nearly 2.5 times more likely to be abstinent than smokers with the opposite brain reactivity profile (11% vs. 4.5%). Although this result was not statistically significant, it suggests our neuroimaging-based classification algorithm can potentially contribute to the development of new precision medicine interventions aimed at treating substance use disorders. Regardless, these findings are still preliminary and in need of confirmation in larger trials., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The rate of nicotine metabolism, estimated by the nicotine metabolite ratio (NMR), is an important determinant of tobacco dependence. This study investigated the effect of NMR on smoking behavior due to nicotine reinforcement during ad libitum smoking., Aims and Methods: As part of a larger study, participants were stratified based on saliva NMR as fast and slow metabolizers. After smoking a cigarette and measuring nicotine blood concentrations, participants smoked as desired over a 90-minute period. Analysis included time to first cigarette, total number of cigarettes, total number of puffs, and weight of tobacco consumed., Results: Sixty-one (48%) participants were fast metabolizers and 66 (52%) slow metabolizers by NMR. No significant differences were found regarding the smoking topography variables by NMR. Normal metabolizers by genotype (n = 79) had a shorter time to first cigarette than reduced metabolizers (n = 39; p = .032). Blacks smoked fewer cigarettes (p = .008) and took fewer total puffs (p = .002) compared with Whites. Among Whites, fast metabolizers by NMR had a shorter time to first cigarette compared with slow metabolizers (p = .014). Among fast metabolizers, Whites had, compared with Blacks, shorter latency to first cigarette (p = .003) and higher number of total puffs (p = .014) and cigarettes smoked (p = .014). Baseline cigarettes per day and nicotine elimination half-life significantly predicted topography outcomes., Conclusions: Saliva NMR did not predict cigarette reinforcement during a relatively brief period of ad libitum smoking. Differences were seen by race, with White fast metabolizers by NMR having shorter time to first cigarettes compared with slow metabolizers., Implications: After a 90-minute period of nicotine abstinence, NMR was not significantly associated with smoking reinforcement. Slow and fast metabolizers had similar time to first cigarette, number of cigarettes smoked, total number of puffs, and tobacco consumed; however, within-race differences show that within Whites, fast metabolizers had a faster time to first cigarette than slow metabolizers., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The endocannabinoid enzyme, fatty acid amide hydrolase (FAAH), has been proposed as a therapeutic target for alcohol use disorder (AUD) and co-morbid psychiatric illnesses. Investigating this target in the living human brain and its relationship to clinical outcome is a critical step of informed drug development. Our objective was to establish whether brain FAAH levels are low in individuals with AUD and related to drinking behavior. In this pilot study, treatment-seeking patients with AUD completed two PET scans with the FAAH radiotracer [C-11]CURB after 3-7 days (n = 14) and 2-4 weeks (n = 9) of monitored abstinence. Healthy controls (n = 25) completed one scan. FAAH genetic polymorphism (rs324420) and blood concentrations of anandamide and other N-acylethanolamines metabolized by FAAH were determined and AUD symptoms assessed. In AUD, brain FAAH levels were globally lower than controls during early abstinence (F(1,36) = 5.447; p = 0.025)) and FAAH substrates (anandamide, oleoylethanolamide, and N-docosahexaenoylethanolamide) were significantly elevated (30-67%). No significant differences in FAAH or FAAH substrates were noted after 2-4 weeks abstinence. FAAH levels negatively correlated with drinks per week (r = -0.57, p = 0.032) and plasma concentrations of the three FAAH substrates (r > 0.57; p < 0.04)). Our findings suggest that early abstinence from alcohol in AUD is associated with transiently low brain FAAH levels, which are inversely related to heavier alcohol use and elevated plasma levels of FAAH substrates. Whether low FAAH is an adaptive beneficial response to chronic alcohol is unknown. Therapeutic strategies focusing on FAAH inhibition should consider the possibility that low FAAH during early abstinence may be related to drinking.

Background: Medications for smoking cessation are currently only effective in helping a minority of smokers quit. Drug development is slow and expensive; as such, there is much interest in optimizing the effectiveness of existing treatments and medications. Current standard doses of nicotine replacement therapy are not effective for many smokers, and in many cases, the amount of nicotine provided is much less than when a smoker is smoking their usual number of cigarettes. The proposed study will test if titrating the dose of the nicotine patch (up to 84 mg) will improve quitting success compared to those receiving a 21-mg nicotine patch with increasing doses of placebo patch., Methods: This is a multicenter, pragmatic, two-arm, placebo-controlled, block randomized controlled trial. We will recruit participants who smoke at least 10 cigarettes daily and are interested in making a quit attempt. After 2 weeks of usual treatment with a 21-mg patch, participants who fail to quit smoking (target n = 400) will be randomized to receive escalating doses of a nicotine patch vs matching placebo patches for an additional 10 weeks or up to a maximum dose of 84 mg per day. Those who stop smoking during the first 2 weeks of usual treatment will continue with 21 mg patch treatment for 10 weeks and will form an additional comparison arm. In addition to the medication, participants will receive brief behavioral counseling at each study visit. The primary outcome will be biochemically confirmed continuous abstinence from smoking during the last 4 weeks of treatment (weeks 9 to 12)., Discussion: Research evidence supporting the effectiveness of personalized doses of nicotine replacement therapy could change current practice in a variety of healthcare settings. Given the evidence that quitting smoking at any age diminishes the risk of tobacco-related morbidity and mortality, even small increases in absolute quit rates can have a substantial population-level impact on reducing smoking-related disease, mortality rates, and associated healthcare costs., Trial Registration: ClinicalTrials.gov, NCT03000387 . Registered on 22 December 2016.

CYP2D metabolizes many drugs that act within the brain, and variable expression of CYP2D in the brain may alter local drug and metabolite levels sufficiently to affect behavioral responses. Transgenic mice that express human CYP2D6 (TG) were compared to wild type mice (WT). Following selective inhibition of human CYP2D6 in TG brain, we demonstrated in vivo that human CYP2D6 in the brain was sufficient to alter a drug-induced behavioral response. After a 4-h pre-treatment with intracerebroventricular (i.c.v.) propranolol, CYP2D activity in vivo and in vitro was reduced in TG brain, whereas CYP2D activity in vivo, but not in vitro, was reduced in WT brain. After a 24-h pre-treatment with i.c.v. propranolol, CYP2D activity in vivo and in vitro was reduced in TG brain, whereas CYP2D activity in vivo and in vitro was not changed in WT brain. These results indicate that i.c.v. propranolol irreversibly inhibited human CYP2D6 in TG brain but not mouse CYP2D in TG and WT brain. Pre-treatments with propranolol did not change liver CYP2D activity in vivo or in vitro. Furthermore, 24-h pre-treatment with i.c.v. propranolol resulted in a significant decrease of the haloperidol-induced catalepsy response in TG, but not in WT, without changing serum haloperidol levels in either mouse line. These studies reveal a new tool to selectively and irreversibly inhibit human CYP2D6 in TG brain and indicate that human CYP2D6 has a functional role within the brain sufficient to impact the central nervous system response from peripherally administered drugs.

Introduction: Alaska Native and American Indian (AN/AI) populations have higher tobacco use prevalence than other ethnic/racial groups. Pharmacogenetic testing to tailor tobacco cessation treatment may improve cessation rates. This study characterized polymorphic variations among AN/AI people in genes associated with metabolism of nicotine and drugs used for tobacco cessation., Methods: Recruitment of AN/AI individuals represented six subgroups, five geographic subgroups throughout Alaska and a subgroup comprised of AIs from the lower 48 states living in Alaska. We sequenced the CYP2A6 and CYP2B6 genes to identify known and novel gain, reduced, and loss-of-function alleles, including structural variation (eg, gene deletions, duplications, and hybridizations)., Results: Variant allele frequencies differed substantially between AN/AI subgroups. The gene deletion CYP2A6*4 and reduced function CYP2A6*9 alleles were found at high frequency in Northern/Western subgroups and in Lower 48/Interior subgroups, respectively. The reduced function CYP2B6*6 allele was observed in all subgroups and a novel, predicted reduced function CYP2B6 variant was found at relatively high frequency in the Southeastern subgroup., Conclusions: Diverse CYP2A6 and CYP2B6 variation among the subgroups highlight the need for comprehensive pharmacogenetic testing to guide tobacco cessation therapy for AN/AI populations., Implications: Nicotine metabolism is largely determined by CYP2A6 genotype, and variation in CYP2A6 activity has altered the treatment success in other populations. These findings suggest pharmacogenetic-guided smoking cessation drug treatment could provide benefit to this unique population seeking tobacco cessation therapy., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

Background: Adherence to nicotine patches relates to cessation. This is the first study to examine the validity of self-reported nicotine patch adherence relative to saliva cotinine., Methods: We used data from 198 clinical trial participants who received 11 weeks of nicotine patches, self-reported patch use, had saliva cotinine 1-week after the start of treatment assessed, and were not smoking when saliva was collected (CO < 6). Self-reported patch adherence was defined as: 3-day (before saliva collection), 7-day (before saliva collection), 3-week use (7 days before, and 14 days after, saliva collection), and 11-week use (7 days before, and 10 weeks after, saliva collection). Analyses, including receiver operating characteristic curves, considered differences in nicotine metabolism. Sensitivity, specificity and positive (PPV) and negative predictive value (NPV) assessed optimal cotinine cut-point for adherence., Results: Self-reported 7-day (r = 0.13) and 3-week (r = 0.13) patch use marginally correlated with week 1 cotinine (p's = 0.08) but not 3-day or 11-week. Significant area under the curve (AUC) values of 0.67 (95 %CI: 0.55-0.79) and 0.72 (95 %CI: 0.57-0.88) were found using 7-day self-report for the overall sample and for slow metabolizers (p's<0.01), but not for normal metabolizers. Optimal 1-week cotinine cut-points using 7-day self-report were 170 ng/mL (overall) and 184 ng/mL (slow), with sensitivity = 0.56-0.62, specificity = 0.69-0.78, PPV = 0.96-0.97, and NPV = 0.13-0.14., Conclusions: Among CO-confirmed abstainers, self-reported patch use and saliva cotinine assessed 1-week into treatment, were modestly correlated and optimal cotinine cut-point differed by rate of nicotine metabolism. Seven-day patch use may be a more valid self-report measure of patch adherence based on cotinine than 3-day, 3-week, or 11-week. Rate of nicotine metabolism may affect this relationship., Competing Interests: Declaration of Competing Interest Dr. Schnoll and Dr. Hitsman have received medication and placebo free from Pfizer and have provided consultation to Pfizer. Dr. Schnoll has provided consultation to GlaxoSmithKline and CuraLeaf. Dr. Gross serves on a DSMB for a Pfizer medication unrelated to smoking. Dr. Benowitz is a consultant to Pfizer and Achieve Life Sciences, companies that market or are developing smoking cessation medications, and has been an expert witness against tobacco companies. Dr Tyndale has consulted for Quinn Emanuel and Ethismos Research Inc., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The endocannabinoid and dopaminergic systems have independently been implicated in substance use disorder and obesity. We investigated a potential interaction between genetically inherited variation in fatty acid amide hydrolase (FAAH, C385A), which metabolizes the cannabis-like endocannabinoid anandamide, and dopaminergic system, measured by dopamine receptor levels and mRNA. Binding of the dopamine D3 preferring probe [C-11]-(+)-PHNO was measured with positron emission tomography (PET) in 79 human subjects genotyped for the FAAH C385A polymorphism (36/79 AC + AA). Autoradiography with [H-3]-(+)-PHNO and in situ hybridization with a D3-specific S-35 riboprobe were carried out in 30 knock-in mice with the FAAH C385A polymorphism (20/30 AC + AA). We found that the FAAH genetic variant C385A was associated with significantly higher (+)-PHNO binding in both humans and in knock-in mice, and this effect was restricted to D3 selective brain regions (limbic striatum, globus pallidus, and ventral pallidum (9-14%; p < 0.04) in humans and Islands of Calleja (28%; p = 0.036) in mice). In situ hybridization with a D3-specific S-35 riboprobe in FAAH knock-in C385A mice confirmed significantly increased D3 receptor mRNA across examined regions (7-44%; p < 0.02). The association of reduced FAAH function with higher dopamine D3 receptors in human and mouse brain provide a mechanistic link between two brain systems that have been implicated in addiction-risk. This may explain the greater vulnerability for addiction and obesity in individuals with C385A genetic variant and by extension, suggest that a D3 antagonism strategy in substance use disorders should consider FAAH C385A polymorphism.

Depression and anxiety are more common among females than males and represent a leading cause of disease-related disability in women. Since the dopamine D1-D2 heteromer is involved in depression- and anxiety-like behavior, the possibility that the receptor complex may have a role in mediating sex differences in such behaviors and related biochemical signaling was explored.In non-human primate caudate nucleus and in rat striatum, females expressed higher density of D1-D2 heteromer complexes and a greater number of D1-D2 expressing neurons compared to males. In rat, the sex difference in D1-D2 expression levels occurred even though D1 receptor expression was lower in female than in male with no difference in D2 receptor expression. In behavioral tests, female rats showed faster latency to depressive-like behavior and a greater susceptibility to the pro-depressive and anxiogenic-like effects of D1-D2 heteromer activation by low doses of SKF 83959, all of which were ameliorated by the selective heteromer disrupting peptide, TAT-D1. The sex difference observed in the anxiety test correlated with differences in low-frequency delta and theta oscillations in the nucleus accumbens. Analysis of signaling pathways revealed that the sex difference in D1-D2 heteromer expression led to differences in basal and heteromer-stimulated activities of two important signaling pathways, BDNF/TrkB and Akt/GSK3/β-catenin.These results suggest that the higher D1-D2 heteromer expression in female may significantly increase predisposition to depressive-like and anxiety-like behavior in female animals.

Introduction: Alcohol may influence the nicotine metabolite ratio (NMR), an index of the rate of nicotine metabolism that is associated smoking level and lapses. We examined if NMR changes during alcohol use disorder (AUD) treatment and how changes in NMR relate to reductions in drinking., Methods: Using an observational design, 22 daily smokers [63.64% male, Mage = 46.77 (11.37)] receiving AUD treatment completed baseline and follow-up appointments 3 weeks apart. At each appointment, daily alcohol and cigarette use, salivary and urinary NMR, nicotine exposure via urinary total nicotine equivalents, and carbon monoxide were assessed. Multilevel models examined the change over time in NMR and its within-person relations with changes in drinks per week. Sex differences were evaluated., Results: There were significant reductions in both salivary and urinary NMR over time for men (p = .02; p = .01, respectively) but not for women (p = .54; p = .90, respectively). There were no changes over time in total nicotine equivalents (p = .09), carbon monoxide (p = .44), or cigarette use (p = .44) in either sex. Drinks per week were significantly reduced for men (29.12 drink reduction, p < .001) but not for women (2.28 drink reduction, p = .80); however, within-person changes in drinking were not associated with changes in salivary or urinary NMR (p = .99; p = .19)., Conclusions: The reduction in alcohol use and NMR in men provides indirect support for alcohol increasing NMR. In contrast, the low baseline drinking and lack of alcohol reduction likely underlie the lack of change in NMR in females. Reasons for NMR reductions during AUD treatment and its effects on smoking require further study., Implications: Three weeks of alcohol use disorder treatment among daily smokers coincided with a significant reduction in both alcohol use and NMR for men; however, neither drinking level nor NMR changed for women. The findings indirectly support that heavy drinking increases NMR, which is reversed with reduced drinking. Additional research is needed to establish if these changes in NMR correlate with smoking and cessation outcomes., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: One of the preferable flavors in oral nicotine delivery systems is menthol which masks the harshness of tobacco. However, possible interactions between oral menthol and nicotine on intake and preference remain unclear. Therefore, we aimed to determine the impact of menthol on oral nicotine consumption., Methods: Adult Sprague Dawley female and male rats (n = 8 per group) were given a choice of water or drug solution by using two-bottle free choice paradigm for 2 weeks: vehicle (5% ethanol), nicotine (20 mg/L), menthol (1 g/L) and mentholated nicotine groups. At the end of the study, plasma nicotine levels were determined., Results: When rats were given a choice of nicotine or water, nicotine intake was similar between female and male rats. Menthol addition to nicotine solution significantly increased nicotine intake and preference in male but not female rats without a considerable effect on total fluid intake and body weight change in either sex. The average nicotine intake in male rats was 0.5 ± 0.05 and 1.4 ± 0.12 mg/kg/day for nicotine and menthol-nicotine combination (p < .05), respectively. The average nicotine intake in female rats was 0.6 ± 0.05 and 0.6 ± 0.03 mg/kg/day for nicotine and menthol-nicotine combination (p > .05), respectively. Plasma nicotine levels were not significantly different between the groups in either male (nicotine group: 20.8 ± 4.9, mentholated nicotine group: 31.9 ± 3.2 ng/mL) or female (nicotine group: 24.0 ± 3.3, mentholated nicotine group: 17.8 ± 2.9 ng/mL) rats (p > .05)., Conclusions: Menthol increases oral nicotine consumption in male, but not female, rats., Implications: This study may provide data on the co-use of menthol and nicotine in smokeless tobacco, particularly oral dissolvable tobacco products., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: Genetics and drug interactions contribute to large interindividual variation in human CYP2D6 activity. Here, we have characterized propranolol inhibition of human and mouse CYP2D using transgenic (TG) mice, which express both mouse CYP2D and human CYP2D6, and wild-type (WT) mice. Our purpose was to develop a method for in vivo manipulation of CYP2D6 enzyme activity which could be used to investigate the role of CYP2D6 in drug-induced behaviours., Experimental Approach: Dextromethorphan metabolism to dextrorphan was used to measure CYP2D activity and to characterize propranolol inhibition in vitro and in vivo. Effects of propranolol pretreatment (24 hr) on serum levels of the CYP2D6 substrate haloperidol and haloperidol-induced catalepsy were also studied., Key Results: Dextrorphan formation velocity in vitro was threefold higher in liver microsomes of TG compared to WT mice. Propranolol acted as a mechanism-based inhibitor (MBI), inactivating CYP2D in liver microsomes from TG and WT mice, and humans. Pretreatment (24 hr) of TG and WT mice with 20 mg·kg -1 intraperitoneal propranolol reduced dextrorphan formation in vivo and by liver microsomes in vitro. Serum haloperidol levels and catalepsy were increased., Conclusions and Implications: Propranolol was a potent MBI of dextrorphan formation in liver microsomes from TG and WT mice, and humans. The inhibition parameters in TG overlapped with those in WT mice and in humans. Inhibition of CYP2D with propranolol in vivo in TG and WT mice altered drug responses, allowing further investigation of variations in CYP2D6 on drug interactions and drug responses., (© 2019 The British Pharmacological Society.)

The nicotine metabolite ratio (NMR; 3-hydroxycotinine/cotinine) is an index of CYP2A6 activity. CYP2A6 is responsible for nicotine's metabolic inactivation and variation in the NMR/CYP2A6 is associated with several smoking behaviors. Our aim was to integrate established alleles and novel genome-wide association studies (GWAS) signals to create a weighted genetic risk score (wGRS) for the CYP2A6 gene for European-ancestry populations. The wGRS was compared with a previous CYP2A6 gene scoring approach designed for an alternative phenotype (C2/N2; cotinine-d2/(nicotine-d2 + cotinine-d2)). CYP2A6 genotypes and the NMR were assessed in European-ancestry participants. The wGRS training set included N = 933 smokers recruited to the Pharmacogenetics of Nicotine Addiction and Treatment clinical trial [NCT01314001]. The replication cohort included N = 196 smokers recruited to the Quit 2 Live clinical trial [NCT01836276]. Comparisons between the two CYP2A6 phenotypes and with fractional clearance were made in a laboratory-based pharmacokinetic study (N = 92 participants). In both the training and replication sets, the wGRS, which included seven CYP2A6 variants, explained 33.8% (P < 0.001) of the variance in NMR, providing improved predictive power to the NMR phenotype when compared with other CYP2A6 gene scoring approaches. NMR and C2/N2 were strongly correlated to nicotine clearance (ρ = 0.70 and ρ = 0.79, respectively; P < 0.001), and to one another (ρ = 0.82; P < 0.001); however reduced function genotypes occurred in slow NMR but throughout C2/N2. The wGRS was able to predict smoking quantity and nicotine intake, to discriminate between NMR slow and normal metabolizers (AUC = 0.79; P < 0.001), and to replicate previous NMR-stratified cessation outcomes showing unique treatment outcomes between metabolizer groups., (© 2019 Society for the Study of Addiction.)

Background and Aims: Varenicline effectiveness may be related to the level of adherence, which might be reduced by adverse effects such as nausea. The aim of the study was to test a possible effect of nausea on smoking cessation outcomes mediated by adherence., Design: Mediation path analysis., Setting: Multiple sites within Canada and the United States., Participants: Treatment-seeking smokers receiving varenicline from two smoking cessation clinical trials: Quit2Live (NCT01836276; n = 449) and Pharmacogenetics of Nicotine Addiction Treatment (PNAT) (NCT01314001; n = 421)., Measurements: Nausea severity was collected through self-report and adherence was biologically assessed using varenicline concentrations (Quit2Live, plasma sample at week 4; PNAT, saliva sample at week 2). In Quit2Live, the end-points were cotinine-verified abstinence at weeks 4, 12 and 26. In PNAT, the end-points were carbon monoxide-verified abstinence at weeks 2, 12 and 26., Findings: Early nausea was not directly associated with abstinence [odds ratio (OR) ranging from 0.73-1.28; P ≥ 0.26]. However early nausea was indirectly associated with lower cessation rates at multiple timepoints (ORs ranging from 0.92-0.94; 95% CI between 0.83-0.99) in a relationship mediated by reduced varenicline adherence (assessed by plasma varenicline concentrations) in the primary trial (Quit2Live). This relationship between nausea, adherence and cessation was similar in direction but weaker in effect size (ORs ranging from 0.98-0.99; 95% CI between 0.90-1.03) in a secondary trial (PNAT), where adherence was assessed using salivary varenicline concentrations., Conclusions: These data suggest that early nausea during varenicline treatment may be indirectly associated with lower likelihood of smoking cessation through reducing varenicline adherence. Differences in robustness between the trials may be due to the different biological matrices (plasma vs. saliva) and/or timing used to assess varenicline adherence. The results of the first study suggest that improved management of early nausea during varenicline treatment may positively impact smoking cessation success through increasing varenicline adherence., (© 2019 Society for the Study of Addiction.)

Introduction: Pregnancy-induced increases in nicotine metabolism may contribute to difficulties in quitting smoking during pregnancy. However, the time course of changes in nicotine metabolism during early and late pregnancy is unclear. This study investigated how pregnancy alters the nicotine metabolite ratio (NMR), a common biomarker of nicotine metabolism among nonpregnant smokers., Methods: Urinary NMR (trans-3'-hydroxycotinine [3HC]/cotinine [COT]) was assessed using total (free + glucuronide) and free compounds among women (N = 47) from a randomized controlled trial for smoking cessation who self-reported smoking and provided a urine sample during early pregnancy (M ± SD = 12.5 ± 4.5 weeks' gestation), late pregnancy (28.9 ± 2.0 weeks' gestation), and 6 months postpartum (24.7 ± 1.2 weeks since childbirth). Urine samples were analyzed using liquid chromatography-tandem mass spectrometry and NMR were calculated as Total 3HC/Free COT, Free 3HC/Free COT, and Total 3HC/Total COT., Results: NMR was significantly higher during early and late pregnancy compared to postpartum and significantly increased from early to late pregnancy as measured by Total 3HC/Free COT (0.76, 0.89, 0.60; all p's < .05) and Free 3HC/Free COT (0.68, 0.80, 0.51; all p's < .05). Total 3HC/Total COT did not vary over time (p = .81)., Conclusions: Total 3HC/Free COT and Free 3HC/Free COT increased in the first trimester and continued to increase throughout pregnancy, suggesting a considerable increase in nicotine metabolism over gestation. Future analyses are needed to interpret the changes in NMR in the context of nicotine pharmacokinetics, as well as its impact on changes in smoking behavior and cessation outcomes., Implications: We observed that the NMR was significantly higher as early as 12 weeks' gestation and increased further as a function of gestational age. Among nonpregnant smokers, elevated NMR is associated with smoking phenotypes such as smoking more cigarettes per day and poorer response to nicotine patch; therefore, pregnancy-induced increases in the NMR may contribute to smoking during the first trimester of pregnancy and reducing or quitting smoking may become more challenging as the rate of nicotine metabolism accelerates over the course of pregnancy., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Here we present new and original data on the endogenous conversion of tyrosol (Tyr) into hydroxytyrosol (OHTyr) in humans and its effects on the cardiovascular system. A randomized, crossover, controlled clinical trial was performed with individuals at cardiovascular risk (n = 33). They received white wine (WW) (females 1, males 2 standard drinks/day), WW plus Tyr capsules (WW + Tyr) (25mg Tyr capsule, one per WW drink), and water (control) ad libitum . Intervention periods were of 4 weeks preceded by three-week wash-out periods. We assessed the conversion of Tyr to OHTyr, its interaction with a polygenic activity score (PAS) from CYP2A6 and CYP2D6 genotypes, and the effects on cardiovascular risk markers. For further details and experimental findings please refer to the article "Cardiovascular benefits of tyrosol and its endogenous conversion into hydroxytyrosol in humans. A randomized, controlled trial" [1]., (© 2019 The Author(s).)

Background: Blacks bear a disproportionate burden of smoking-related diseases and experience greater difficulty quitting smoking than Whites. Nicotine has a high affinity for melanin, and it has been hypothesized that melanin levels might influence nicotine pharmacokinetics and enhance dependence. The aim of this study was to evaluate the hypothesis that melanin affects nicotine disposition kinetics in humans., Methods: Forty-four Black participants were administered intravenous infusions of deuterium-labeled nicotine and cotinine. Plasma concentrations of nicotine and cotinine were measured, and pharmacokinetic parameters were estimated. The constitutive and facultative melanin indexes were measured using a dermaspectrophotometer., Results: The median constitutive melanin index was 60.7 (32.8-134.7) and the median facultative melanin index 68.1 (38.6-127.1). The mean (±SD) nicotine elimination half-life was 136 min (±33.5), clearance was 1237 mL/min (±331), and V ss was 204 L (±66), or 2.6 L/kg (±0.7). No evidence of significant differences was found in nicotine pharmacokinetic parameters by comparing participants in different melanin index quartiles (outliers with very high melanin index had similar pharmacokinetic values to others). Differences were not statistically significant when adjusted for age, BMI, sex and CYP2A6 genotype or the nicotine metabolite ratio (NMR), and no evidence of significant correlations were found between melanin (facultative or constitutive) and the pharmacokinetic parameters of nicotine or cotinine or tobacco dependence measures., Conclusions: Based on our finding in this group of Black smokers, we could not confirm the hypothesis that melanin significantly affects nicotine disposition kinetics or measures of tobacco dependence., (Copyright © 2019. Published by Elsevier B.V.)

Introduction: The simple phenol hydroxytyrosol (OHTyr) has been associated with the beneficial health effects of extra virgin olive oil. Pre-clinical studies have identified Tyr hydroxylation, mediated by cytochrome P450 isoforms CYP2A6 and CYP2D6, as an additional source of OHTyr., Aim: We aimed to (i) confirm Tyr to OHTyr bioconversion in vivo in humans, (ii) assess the cardiovascular benefits of this bioconversion, and (iii) determine their interaction with a polygenic activity score (PAS) from CYP2A6 and CYP2D6 genotypes., Methods: Randomized, crossover, controlled study. Individuals at cardiovascular risk (n = 33) received: white wine (WW) (females 1, males 2 standard drinks/day), WW plus Tyr capsules (WW + Tyr) (25  mg Tyr capsule, one per WW drink), and water (control) ad libitum. Participants were classified by a PAS as low versus normal activity metabolizers., Results: OHTyr recovery following WW + Tyr was higher than after other interventions (P < 0.05). Low PAS individuals had lower OHTyr/Tyr ratios compared to individuals with normal PAS. WW + Tyr improved endothelial function, increased plasma HDL-cholesterol and antithrombin IIII, and decreased plasma homocysteine, endothelin 1, and CD40L, P65/RELA, and CFH gene expression in peripheral blood mononuclear cells (p < 0.05). Combining Tyr capsule(s) with WW abolished the increase in iNOS, eNOS, VEGFA, and CHF expressions promoted by WW (p < 0.05)., Conclusions: Tyr, and its partial biotransformation into OHTyr, promoted cardiovascular health-related benefits in humans after dietary doses of Tyr. The study design allowed the health effects of individual phenols to be singled out from the dietary matrix in which they are naturally found., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: The study objective was to identify biobehavioral variables associated with greater intake of nicotine and a tobacco carcinogen among Black light smokers who smoke 1 to 10 cigarettes per day (CPD)., Methods: We analyzed baseline data collected from 426 Black light smokers enrolled in Kick It at Swope III (KIS III), a smoking cessation trial for Black smokers. We examined differences in concentrations of tobacco biomarkers, including urinary total nicotine equivalents (TNE) and total 4-(methylnitrosamino)-1-(3)pyridyl-1-butanonol (NNAL; a human carcinogen), across gender, age, plasma nicotine metabolite ratio (NMR), CPD, and measures of tobacco dependence, including time to first cigarette (TFC), using ANOVA., Results: Tobacco biomarker levels were significantly higher among those who smoked more CPD (6-10 vs 1-5 CPD) and those with greater reported physical dependence on tobacco. Concurrently, those who smoked 1-5 CPD smoked each cigarette more intensely than those who smoked 6-10 CPD. While we found no gender differences overall, among those who smoked 1-5 CPD, women had higher NNAL levels compared to men. The rate of nicotine metabolism, measured by the nicotine metabolite ratio, was not significantly related to TNE or NNAL levels., Conclusion: Among Black Light smokers, higher cigarette consumption and greater physical dependence-but not rate of nicotine metabolism, menthol use, or socioeconomic status-were associated with greater toxicant exposure and thus a likely increased risk of tobacco-related diseases. The lack of data on light smokers, and specifically on Blacks, make this observation important given the disproportionate burden of lung cancer in this population., (Copyright © 2019 National Medical Association. Published by Elsevier Inc. All rights reserved.)

The HIV type-1 nonnucleoside reverse transcriptase inhibitor, efavirenz, is widely used to treat HIV type-1 infection. Efavirenz is predominantly metabolized into inactive metabolites by cytochrome P450 (CYP)2B6, and patients with certain CYP2B6 genetic variants may be at increased risk for adverse effects, particularly central nervous system toxicity and treatment discontinuation. We summarize the evidence from the literature and provide therapeutic recommendations for efavirenz prescribing based on CYP2B6 genotypes., (© 2019 The Authors Clinical Pharmacology & Therapeutics  © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Background: Black-white differences in smoking abstinence are not well understood. This trial sought to confirm previously reported differences in quitting between blacks and whites and to identify factors underlying this difference., Methods: During enrollment, 224 black and 225 white low-income smokers were stratified on race and within race on age and sex to ensure balance on these factors known to impact abstinence. The intervention included varenicline for 12 weeks and six guideline-based smoking cessation counseling sessions. The primary endpoint was cotinine-verified 7-day point prevalence smoking abstinence at week 26. A priori socioeconomic, smoking, treatment process (eg, treatment utilization, side effects, withdrawal relief), psychosocial, and biological factors were assessed to investigate race differences in abstinence. Unadjusted odds ratios (OR) were used to compare abstinence between blacks and whites. Adjusted odds ratios from logistic regression models were used to examine predictors of abstinence. All statistical tests were two-sided., Results: Blacks were less likely to achieve abstinence at week 26 (14.3% vs 24.4%, OR = 0.51, 95% confidence interval [CI] = 0.32 to 0.83, P = .007). Utilizing best subsets logistic regression, five factors associated with race jointly predicted abstinence: home ownership (yes/no, OR = 3.03, 95% CI = 1.72 to 5.35, P < .001), study visits completed (range = 0-6, OR = 2.81, 95% CI = 1.88 to 4.20, P < .001), income (household member/$1000, OR = 1.03, 95% CI = 1.01 to 1.06, P = .02), plasma cotinine (per 1 ng/mL, OR = 0.997, 95% CI = 0.994 to 0.999, P = .002), and neighborhood problems (range = 10-30, OR = 0.88, 95% CI = 0.81 to 0.96, P = .003)., Conclusions: The race difference in abstinence was fully explained by lack of home ownership, lower income, greater neighborhood problems, higher baseline cotinine, and higher visit completion, which were disproportionately represented among blacks. Findings illuminate factors that make it harder for blacks in the United States to quit smoking relative to whites and provide important areas for future studies to reduce tobacco-related health disparities., (© The Author, 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Tobacco smoking is the major cause of disability and death in the United States and around the world. In addition, tobacco dependence and addiction express themselves as complex behaviors involving an interplay of genetics, environment, and psychological state. Mouse genetic studies could potentially elucidate the novel genes and/or gene networks regulating various aspects of nicotine dependence. Using the closely related C57BL/6 (B6) mice substrains, recent reports have noted phenotypic differences within C57BL/6J (B6J) and C57BL/6N (B6N) mice for some drugs of abuse: alcohol, opiates, and cocaine. However, the differences in nicotine's effects have not yet been described in these substrains. We examined the phenotypic differences in these substrains following the acute and repeated administration of nicotine in several pharmacological measures, including locomotion (after acute and repeated exposure), body temperature, nociception, and anxiety-like behaviors. We report substrain differences in the pharmacological effects of acute and repeated nicotine administration in the B6 substrains. Overall, we show enhanced nicotine sensitivity to locomotion, hypothermia, antinociception, and anxiety-like behaviors in the B6J mouse substrain compared to B6N. In the repeated administration paradigm, both the B6N and B6J substrains showed no sensitized locomotor responses after repeated exposure to nicotine at the two doses tested. This study thus provides evidence that the B6 mouse substrains may be useful for genetic studies to elucidate some of the genetic variants involved in tobacco dependence and addiction.

Smoking-induced relief of craving and withdrawal promotes continued cigarette use. Understanding how relief is produced and the role of nicotine in this process may facilitate development of new smoking-cessation therapies. As the US Food and Drug Administration considers setting a standard for reduced nicotine content in cigarettes to improve public health, knowledge of how nicotine contributes to relief also can inform policy. We assessed effects of nicotine using resting state functional magnetic resonance imaging (MRI) and behavioral assessments of craving and negative affect. Twenty-one young (18-25 years old) daily smokers underwent overnight abstinence on 4 days. On each of the following mornings, they self-rated their cigarette craving and negative affect and underwent resting-state functional MRI (fMRI) before and after smoking a cigarette that delivered 0.027, 0.110, 0.231, or 0.763 mg of nicotine. Functional connectivity between the anterior insula and anterior cingulate cortex (ACC) and between the nucleus accumbens and orbitofrontal cortex (OFC) was assessed. Smoking reduced craving, negative affect, and nucleus accumbens-OFC connectivity irrespective of nicotine dose, with positive correlations of the effects on behavioral and connectivity measures. Only the highest nicotine dose (0.763 mg) reduced right anterior insula-ACC connectivity; this reduction was positively correlated with the behavioral effects of the 0.763-mg dose only. While nicotine-based therapies may act on right anterior insula-ACC functional circuits to facilitate smoking cessation, non-nicotine (eg, the conditioned and sensorimotor) aspects of smoking may promote cessation by reducing OFC-accumbens connectivity to alleviate withdrawal., (© 2018 Society for the Study of Addiction.)

Background: Precision interventions using biological data may enhance smoking treatment, yet are understudied among smokers who are disproportionately burdened by smoking-related disease., Methods: We surveyed smokers in the NCI-sponsored Southern Community Cohort Study, consisting primarily of African-American, low-income adults. Seven items assessed attitudes toward aspects of precision smoking treatment, from undergoing tests to acting on results. Items were dichotomized as favorable (5 = strongly agree/4 = agree) versus less favorable (1 = strongly disagree/2 = disagree/3 = neutral); a summary score reflecting generalized attitudes was also computed. Multivariable logistic regression tested independent associations of motivation (precontemplation, contemplation, and preparation) and confidence in quitting (low, medium, and high) with generalized attitudes, controlling for sociodemographic factors and nicotine dependence., Results: More than 70% of respondents endorsed favorable generalized attitudes toward precision medicine, with individual item favorability ranging from 64% to 83%. Smokers holding favorable generalized attitudes reported higher income and education ( P < 0.05). Predicted probabilities of favorable generalized attitudes ranged from 63% to 75% across motivation levels [contemplation vs. precontemplation: adjusted odds ratio (AOR) = 2.10, 95% confidence interval (CI), 1.36-3.25, P = 0.001; preparation vs. precontemplation: AOR = 1.83, 95% CI, 1.20-2.78, P = 0.005; contemplation vs. preparation: AOR = 1.15, 95% CI, 0.75-1.77, P = 0.52] and from 59% to 78% across confidence (medium vs. low: AOR = 1.91, 95% CI, 1.19-3.07, P = 0.007; high vs. low: AOR = 2.62, 95% CI, 1.68-4.10, P < 0.001; medium vs. high: AOR = 0.73, 95% CI, 0.48-1.11, P = 0.14)., Conclusions: Among disproportionately burdened community smokers, most hold favorable attitudes toward precision smoking treatment. Individuals with lower motivation and confidence to quit may benefit from additional intervention to engage with precision smoking treatment., Impact: Predominantly favorable attitudes toward precision smoking treatment suggest promise for future research testing their effectiveness and implementation., (©2019 American Association for Cancer Research.)

Aims: CYP2A6 is a genetically polymorphic enzyme resulting in differential substrate metabolism and health behaviours. Current phenotyping probes for CYP2A6 exhibit limitations related to procurement (deuterated cotinine), toxicity (coumarin), specificity (caffeine) and age-appropriate administration (nicotine, NIC). In vitro, CYP2A6 selectively forms 2-hydroxymetronidazole (2HM) from metronidazole (MTZ). The purpose of this study was to evaluate MTZ as a CYP2A6 phenotyping probe drug in healthy adults against the well-established method of measuring trans-3-hydroxycotinine (3HC)/cotinine (COT)., Methods: A randomized, cross-over, pharmacokinetic study was completed in 16 healthy, nonsmoking adults. Separated by a washout period of at least 2 weeks, MTZ 500 mg and NIC gum 2 mg were administered and plasma was sampled over 48 hours and 8 hours, respectively. Correlations of plasma metabolite/parent ratios (2HM/MTZ; 3HC/COT) were assessed by Pearson coefficient. CYP2A6 genotyping was conducted and incorporated as a variable of plasma ratio response., Results: Correlations between the plasma ratio 2HM/MTZ and 3HC/COT were ≥ 0.9 at multiple time points (P < 0.001), demonstrating a wide window during which 2HM/MTZ can be queried post-MTZ dose. CYP2A6 genotype had significant impacts on both MTZ and NIC phenotyping ratios with decreased activity predicted phenotypes demonstrating 2HM/MTZ ratios ≤58% and 3HC/COT ratios ≤56% compared with extensive activity predicted phenotypes at all time points examined in the study (P < 0.05). No adverse events were reported in the MTZ arm while 38% (n = 6) of participants reported mild adverse events in the NIC arm., Conclusions: Metronidazole via 2HM/MTZ performed well as a novel, safe phenotyping probe for CYP2A6 in healthy adults., (© 2019 The British Pharmacological Society.)

Objective: HIV-infected smokers lose more life years to tobacco use than to HIV infection. The nicotine metabolite ratio (NMR), a biomarker of CYP2A6, represents individual variation in the rate at which nicotine is metabolized and is associated with response to smoking cessation treatments. We evaluated whether HIV-infected smokers metabolize nicotine faster than HIV-uninfected smokers, which may contribute to the disproportionate smoking burden and may have important treatment implications., Design: We analysed baseline data from two clinical trials (NCT01710137; NCT01314001) to compare the NMR in HIV-infected smokers (N = 131) to HIV-uninfected smokers (N = 199)., Methods: Propensity scores were used to match the groups 2 : 1 on characteristics that influence NMR: sex, race, BMI and smoking rate. Nicotine metabolites were assessed via liquid chromatography-tandem mass spectrometry methods and the ratio of 3-hydroxycotinine:cotinine was used to compute the NMR., Results: HIV-infected smokers had significantly higher NMR (mean = 0.47, SEM = 0.02) and were more likely to be in the highest NMR quartile compared with HIV-uninfected smokers (mean = 0.34, SEM = 0.02; Ps < 0.001)., Conclusion: The higher NMR observed among HIV-infected smokers may partially explain higher smoking rates and lower response to transdermal nicotine therapy. Understanding the mechanisms by which HIV and/or ART contribute to faster nicotine metabolism may guide the use of the NMR to personalize tobacco cessation strategies in this underserved population.

This study investigated the influence of the rate of nicotine metabolism, as indicated by the nicotine metabolite ratio (NMR), on tobacco dependence. We stratified 136 smokers on the basis of saliva NMR as fast (n = 65) and slow (n = 71) metabolizers. Two "loading cigarettes" were smoked after overnight, and a "reward cigarette" was smoked after 6 hours of daytime, abstinence. Blood nicotine concentrations, expired carbon monoxide, withdrawal/craving, and reward questionnaires were collected before/after smoking and during daytime abstinence. Compared with slow metabolizers, fast metabolizers had a shorter nicotine elimination half-life (P < 0.001), lower plasma nicotine concentrations (P < 0.001), and higher withdrawal/craving scores (P < 0.05) for most times during daytime abstinence, indicating that fast metabolizers are likely smoking more to relieve withdrawal symptoms (negative reinforcement). Reward/satisfaction scores were similar in fast and slow metabolizers, suggesting that faster nicotine metabolism, assessed by NMR, is not associated with greater positive reinforcement. CYP2A6 normal (n = 82) and reduced (n = 42) genotype predicted plasma nicotine concentrations but not withdrawal symptoms., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

Smokers attempting to quit often attribute smoking relapse to negative affect, craving, and other nicotine withdrawal symptoms. In addition, there is evidence that smoking relapse can increase these symptoms, particularly negative affect. To address this issue, we analyzed data from an 11-week smoking cessation clinical trial in which smokers (n = 1,246) were randomized to receive either nicotine replacement therapy (NRT), varenicline, or placebo, combined with behavioral counseling. Using cross-lagged analyses, we examined the temporal bidirectional relationships between self-reported measures of affect, craving, and composite withdrawal symptoms and biochemically verified smoking abstinence. The relative strength of these temporal relationships was examined by comparing the explained variances of the models. The results showed that higher negative affect, craving, and composite withdrawal symptoms increased the likelihood of subsequent smoking relapse, and that smoking relapse led to subsequent increases in these same symptoms. A comparison of the explained variances found symptom predicting subsequent relapse models to be stronger than those where relapse predicted subsequent symptoms. Although the explained variance findings generally support a negative reinforcement conceptualization of nicotine dependence, the bidirectional relationship between symptoms and smoking relapse suggests that struggling with quitting smoking leads to significant negative affect, craving, and other withdrawal symptoms that do not quickly resolve. These findings highlight the importance of addressing specific symptoms within the context of smoking cessation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

When trying to quit, women are less likely than men to achieve long-term smoking abstinence. Identifying the neuropsychological mechanisms underlying women's higher relapse vulnerability will help clinicians to develop effective tailored smoking cessation interventions. Here we used event-related potentials (ERPs), a direct measure of brain activity, to evaluate the extent to which neurophysiological responses to cigarette-related and other emotional stimuli differ between female and male smokers. Both women and men showed similar patterns of brain reactivity across all picture categories; pleasant and unpleasant images prompted larger Late Positive Potentials (LPPs, a robust measure of motivational relevance) than neutral images in both groups, and cigarette-related images prompted lower LPPs than high arousing emotional images in both groups. Unlike previous studies, there were no differences between male and female smokers with regard to LPP responses to cigarette-related images. This suggests that the LPP may not be ideally suited to discriminate neurophysiological gender differences or that there are simply no gender differences in the neurophysiological responses to cigarette-related stimuli. We collected ERPs from 222 non-nicotine-deprived smokers (101 women) while they watched a slideshow that included high and low emotionally arousing pleasant and unpleasant pictures, cigarette-related, and neutral pictures. We used the mean amplitude of the LPP to assess the affective significance that participants attributed to these pictures.

Oxycodone is metabolized by CYP2D to oxymorphone. Despite oxymorphone being a more potent opioid-receptor agonist, its contribution to oxycodone analgesia may be minor because of low peripheral production, low blood-brain barrier permeability and central nervous system efflux. CYP2D metabolism within the brain may contribute to variation in central oxycodone and oxymorphone levels, thereby affecting analgesia. Brain CYP2D expression and activity are subject to exogenous regulation; nicotine induces rat brain, but not liver, CYP2D consistent with higher brain CYP2D in smokers. We assessed the role of rat brain CYP2D in orally administered oxycodone metabolism (in vivo brain microdialysis) and analgesia (tail-flick test) by inhibiting brain CYP2D selectively with intracerebroventricular propranolol (mechanism-based inhibitor) and inducing brain CYP2D with nicotine. Inhibiting brain CYP2D increased brain oxycodone levels (1.8-fold; P < 0.03) and analgesia (1.5-fold AUC 0-60 ; P < 0.001) after oxycodone, while inducing brain CYP2D increased brain oxymorphone levels (4.6-fold; P < 0.001) and decreased analgesia (0.8-fold; P < 0.02). Inhibiting the induced brain CYP2D reversed the change in oxycodone levels (1.2-fold; P > 0.1) and analgesia (1.1-fold; P > 0.3). Brain, but not plasma, metabolic ratios were affected by pre-treatments. Peak analgesia was inversely correlated with ex vivo brain (P < 0.003), but not hepatic (P > 0.9), CYP2D activity. Altering brain CYP2D did not affect analgesia from oral oxymorphone (P > 0.9 for AUC 0-60 across all groups), which is not a CYP2D substrate. Thus, brain CYP2D metabolism alters local oxycodone levels and response, suggesting that people with increased brain CYP2D activity may have reduced oxycodone response. Factors that alter individual oxycodone response may be useful for optimizing treatment and minimizing abuse liability., (© 2017 Society for the Study of Addiction.)

Background and Aims: In smoking treatment trials comparing varenicline with transdermal nicotine replacement therapy (NRT), stratified by nicotine metabolite (3-hydroxycotinine/cotinine) ratio (NMR), the relative benefit of varenicline is greater among normal rather than slow metabolizers. This study tested if the relative effectiveness of varenicline and NRT is associated with NMR status in a natural treatment setting. A secondary aim was to test if this relationship is moderated by behavioural support., Design: Prospective observational multi-centre study with 4-week and 52-week follow-up., Setting: Nine English Stop Smoking Services (SSS)., Participants: Data came from 1556 smokers (aged ≥ 16 years) attending SSS between March 2012 and March 2013., Interventions: Participants received pharmacotherapy together with behavioural support., Measurements: The primary outcome was carbon monoxide-verified continuous abstinence at both follow-up times. Main explanatory variables were (1) NMR status [slow (NMR < 0.31, n = 451) versus normal (NMR ≥ 0.31, n = 1105) metabolizers]; (2) pharmacotherapy (varenicline versus NRT) and (3) behavioural support (individual versus group-based treatment). Analyses adjusted for baseline socio-demographic, SSS, mental/physical health and smoking characteristics., Findings: Of participants, 44.2% [95% confidence interval (CI) = 41.7-46.6%] and 8.0% (95% CI = 6.8-9.5%) were continuously abstinent at 4 and 52 weeks. Varenicline was more effective than NRT at 4 weeks (P < 0.001) but only marginally so at 52 weeks (P = 0.061). There was no or inclusive evidence that NMR status moderated relative efficacy of varenicline and NRT at 4- [P = 0.60, Bayes factor (BF) = 0.25] or 52-week follow-ups (P = 0.74, BF = 0.73). However, this relationship was moderated by behavioural support (p = 0.012): the relative benefit of varenicline over NRT at 52-week follow-up was greater in slow, not normal, metabolizers receiving group rather than individual support (P = 0.012)., Conclusions: In a real-world setting, the nicotine metabolite ratio status of treatment-seeking smokers does not appear to contribute substantially to the differential effectiveness of varenicline and nicotine replacement therapy in Stop Smoking Services, when both pharmacotherapy and behavioural support are self-selected., (© 2018 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: The nicotine metabolite ratio (NMR) is a biomarker that represents individual variation in the speed that nicotine is metabolized. The rate of nicotine metabolism alters smoking behavior (eg, amount) and has been validated for personalizing tobacco dependence medication selection to increase treatment efficacy and reduce treatment side effects in the general population of smokers. Although smoking rates are extremely high among those with HIV, the NMR has not been evaluated in this underserved population., Methods: We used baseline data from a smoking cessation clinical trial for smokers with HIV (N = 131) to examine associations between NMR and demographic, smoking, disease-related, and psychological characteristics. Pearson r and analysis of variance were used to identify univariate correlates of NMR, which were then entered into a multiple linear regression model., Results: In univariate analyses, a higher NMR (faster nicotine metabolism) was associated with being white, and more cigarettes per day, nicotine dependence, exhaled carbon monoxide, and symptoms of depression and anxiety, and using efavirenz. In a multiple regression model, a higher NMR was associated with more cigarettes per day, higher anxiety symptoms, and efavirenz use., Conclusions: As in other populations, faster nicotine metabolism was associated with the use of more cigarettes and higher anxiety symptoms. Notably, efavirenz use was associated with faster metabolism, which might make it harder to quit smoking for people with HIV treated with that medication. These findings could help guide further study and the clinical use of the NMR to personalize nicotine dependence treatment in this underserved population.