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Cited by 222Smoking Behavior and CessationNicotinic Acetylcholine Receptors StudySubstance Abuse Treatment and Outcomes

Varenicline improves mood and cognition during smoking abstinence

Open access
Patterson, Freda, Jepson, Christopher, Strasser, Andrew A., Loughead, James, Perkins, Kenneth A., Gur, Ruben C., Frey, Joseph M., Siegel, Steven +1 more·2009·Biological Psychiatry
DOI 10.1016/j.biopsych.2008.08.028PMC PMC2615779
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Abstract

Background Neuronal nicotinic acetylcholine receptors (nAChRs) are a key target in medication development efforts for a range of neuropsychiatric disorders, including nicotine dependence. Varenicline, a partial agonist at the α4β2 nAChRs, is a new efficacious medication for nicotine dependence. Its effects on the affective and cognitive dimensions of nicotine withdrawal have yet to be well characterized. Methods Sixty-seven treatment-seeking smokers were administered varenicline (× 21 days) and placebo (× 21 days) in a double-blind within-subject cross-over design. Following the medication run-up phase (days 1–10), there was a 3-day mandatory smoking abstinence phase (days 11–13) during which subjective symptoms and cognitive performance were assessed. Participants were re-exposed to a scheduled smoking lapse (day 14) and followed for days to lapse (days 15–21) in each medication period. Results In the varenicline period, compared to placebo, withdrawal symptoms (p=.04), smoking urges (p<.001), and negative affect (p=.01) were significantly reduced, and levels of positive affect (p=.046), sustained attention (p=.018) and working memory (p=.001) were significantly greater during mandatory abstinence. Varenicline also significantly reduced the subjective rewarding effects of the scheduled smoking lapse (e.g., satisfaction, relief, liking) (p=.003). Medication effects on days to lapse following the scheduled smoking lapse were dependent on treatment order (p=.001); among participants who received placebo in the first period, varenicline increased days of abstinence in the follow-up period. Conclusions These data identify novel affective and cognitive effects of varenicline, and may have implications for medication development for other neuropsychiatric conditions.

AI snapshot

Written from the paper’s full text.

TL;DR

In a double-blind within-subject crossover study of 67 treatment-seeking smokers, varenicline reduced withdrawal, urges, negative affect, and smoking reward while improving positive affect, sustained attention, and working memory during 3-day mandatory abstinence. Varenicline increased days to lapse only among participants who received placebo first, revealing an order-dependent effect.

Key findings

  • During mandatory abstinence (days 11–13), varenicline vs placebo significantly reduced withdrawal symptoms (p=.04), smoking urges (p<.001), and negative affect (p=.013), and increased positive affect (p=.046); effects were small to moderate (Cohen’s d = 0.26–0.42).
  • Varenicline improved cognitive performance: Letter-N-back correct reaction time (F=11.08, p=.001; d=0.21), Penn Continuous Performance Task true positives (F=7.28, p=.009; d=0.33), and CPT correct reaction time (F=5.86, p=.018); no medication effect was found for N-back true positives (p=.98) or the Conditional Exclusion Test.
  • Varenicline attenuated the subjective rewarding value of the scheduled lapse cigarette (F=9.25, p=.003; d=0.36), including satisfaction (p=.002; d=0.43), relief (p=.006; d=0.34), and liking (p=.001; d=0.41).
  • Days to lapse showed a significant treatment-by-order interaction (F=11.99, p=.001): among placebo-first participants, mean days to lapse were 4.63 (SD=2.86) with varenicline vs 2.57 (SD=2.94) with placebo (Z=3.16, p=.002; d=0.71); among varenicline-first participants, means were 4.19 (SD=3.04) vs 4.94 (SD=2.87) (Z=1.34, p=.18; d=−0.25). Side effects reported as moderate or severe by over 5% occurred in 55.2% (37/67) on varenicline vs 28.4% (19/67) on placebo at day 10.

Methods

  • Double-blind, placebo-controlled, within-subject crossover study of 67 treatment-seeking smokers (≥18 years, ≥10 cigarettes/day for previous 12 months; mean age 44.6 years, SD=11.6; 56.7% female; baseline mean 21.5 cigarettes/day, SD=10.0). Participants completed two 21-day medication periods (varenicline and placebo in counterbalanced order) with a 5–7 day washout; varenicline was titrated per standard guidelines, followed by a 10-day run-up, 3-day mandatory abstinence (days 11–13), scheduled smoking lapse (day 14), and follow-up days 15–21.
  • Outcomes included subjective withdrawal symptoms, smoking urges, PANAS positive/negative affect, computerized neurocognitive tasks (Letter-N-back, Penn Continuous Performance Task, Conditional Exclusion Test) at baseline and day 13, Cigarette Evaluation Scale and Sensory Questionnaire after the lapse cigarette, CO-verified abstinence, medication adherence, and side-effect severity.
  • Mixed effects models tested medication effects, controlling for sex, baseline cigarettes per day, and medication order; subjective models also included day 10 (smoking as usual) levels as a time-varying covariate, and neurocognitive models included baseline scores as a time-invariant covariate. Cohen’s d was calculated for raw varenicline–placebo differences.

Limitations

  • The authors state that order effects were observed for the smoking abstinence outcome: varenicline increased days to lapse only among participants who received placebo first, not among those who received varenicline first. They suggest this may reflect greater self-efficacy after varenicline-induced abstinence success or longer-lasting nAChR modulation.
  • The authors note recent reports of adverse psychiatric events with varenicline but state it is not possible to determine whether these events are partly attributable to nicotine withdrawal.
  • Evident from the text: the abstinence phase was only 3 days and lapse follow-up only 7 days; several medication effects were small; the positive affect effect became nonsignificant when side-effect severity was included as a covariate (F=1.62, p=.21); side effects were more common on varenicline, which could affect blinding; and the sample excluded current or historical DSM-IV Axis I psychiatric disorders or substance abuse other than nicotine, limiting generalizability.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.biopsych.2008.08.028

Cites

55 of 55 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

0 of 33 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    During mandatory abstinence, varenicline reduced negative affect compared with placebo (p=.013).

    “During the varenicline period, compared to placebo, participants reported lower levels of withdrawal symptoms (p=.04), smoking urges (p<.001), and negative affect (p=.013).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5–7 day washout period between the two medication periods was sufficient to eliminate carryover effects of varenicline.
  • Findingown data

    During mandatory abstinence, varenicline reduced smoking urges compared with placebo (p<.001).

    “During the varenicline period, compared to placebo, participants reported lower levels of withdrawal symptoms (p=.04), smoking urges (p<.001), and negative affect (p=.013).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5–7 day washout period between the two medication periods was sufficient to eliminate carryover effects of varenicline.
  • Findingown data

    Varenicline reduced liking of the scheduled lapse cigarette (F=11.09, p=.001; d=0.41).

    “Significant effects were observed for satisfaction (F = 10.05, p = .002; d = 0.43), relief (F = 8.12, p = .006; d = 0.34), and liking (F = 11.09, p = .001; d = 0.41).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The 5–7 day washout period between the two medication periods was sufficient to eliminate carryover effects of varenicline.
  • Findingown data

    The effect of medication on days to lapse following the scheduled smoking lapse depended on treatment order (F=11.99, p=.001).

    “For days to lapse in the observation phase (days 15–21), there was a significant treatment by order interaction (F = 11.99, p = .001).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The 5–7 day washout period between the two medication periods was sufficient to eliminate carryover effects of varenicline.
  • Findingown data

    Varenicline reduced satisfaction from the scheduled lapse cigarette (F=10.05, p=.002; d=0.43).

    “Significant effects were observed for satisfaction (F = 10.05, p = .002; d = 0.43), relief (F = 8.12, p = .006; d = 0.34), and liking (F = 11.09, p = .001; d = 0.41).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5–7 day washout period between the two medication periods was sufficient to eliminate carryover effects of varenicline.
  • May combine two claims. 14
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Findingown data

    Varenicline did not affect executive function as measured by CET true positives or correct reaction time; only baseline performance was significant.

    “Only baseline performance was significant in the models of CET true positives (p = .02) and correct reaction time (p < .001).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The 5–7 day washout period between the two medication periods was sufficient to eliminate carryover effects of varenicline.

  • The quote only partly states this claim.

    Findingown data

    Varenicline improved sustained attention as measured by CPT correct reaction time (F=5.86, p=.018).

    “in the model of CPT correct reaction time, there were effects of medication (F = 5.86, p = .018) and baseline performance (F = 117.1, p < .001).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5–7 day washout period between the two medication periods was sufficient to eliminate carryover effects of varenicline.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Varenicline acts as a partial agonist at α4β2 nicotinic acetylcholine receptors and as a full agonist at α7 nicotinic acetylcholine receptors.

    “Varenicline, a partial agonist at the α4β2 nAChRs, and a full agonist at the α7 nAChRs, is a new, efficacious treatment for nicotine dependence (4–6).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Mihalak, 2006, Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors, Mol Pharmacol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Neuronal nicotinic acetylcholine receptors are a key target in medication development for nicotine dependence and other neuropsychiatric conditions.

    “Neuronal nicotinic acetylcholine receptors (nAChRs) are a key target of drug discovery efforts for nicotine dependence, as well as for neuropsychiatric conditions (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Arneric, 2007, Neuronal nicotinic receptors: A perspective on two decades of drug discovery research, Biochem Pharmacol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The subjective scales had acceptable internal consistency, with Cronbach's alphas ranging from .79 to .96.

    “Cronbach’s alphas for all scales ranged from .79 to .96.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The MINI diagnostic interviews were administered by trained technicians, and 10% were recorded and reviewed by a licensed clinician.

    “The MINI International Neuropsychiatric Interview (MINI) was administered by trained research technicians to screen for psychiatric and substance abuse disorders (21). Ten percent of MINI interviews were recorded and reviewed by a licensed clinician.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Sheehan, 1998, The Mini-International Neuropsychiatric Interview (MINI): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10, J Clin Psychiatry

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Neurocognitive outcome models included baseline scores as a time-invariant covariate.

    “The models of neurocognitive outcomes included baseline scores as a time-invariant covariate.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Varenicline produces moderate nicotinic acetylcholine receptor stimulation and lower sustained dopamine release, thereby replacing some effects of nicotine.

    “Varenicline produces a moderate level of nAChR stimulation and lower sustained levels of dopamine release, thereby replacing some of nicotine’s effects (7).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Coe, 2005, Varenicline: An alpha4beta2 nicotinic receptor partial agonist for smoking cessation, J Med Chem source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Apart from urges to smoke, the most common nicotine abstinence symptoms involve emotional dysregulation and cognitive deficits.

    “Aside from urges to smoke, the most common symptoms involve emotional dysregulation and cognitive deficits (13, 14).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Hughes, 2007, Effects of abstinence from tobacco: Valid symptoms and time course, Nicotine Tob Res source

      Not checked in the free run.

    • cites [14] Ward, 2001, Self-reported abstinence effects in the first month after smoking cessation, Addict Behav source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Competitive binding at nicotinic acetylcholine receptors should theoretically reduce nicotine reward.

    “Further, competitive nAChR binding should, theoretically, reduce nicotine reward (7, 8).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Coe, 2005, Varenicline: An alpha4beta2 nicotinic receptor partial agonist for smoking cessation, J Med Chem source

      Not checked in the free run.

    • cites [8] Rollema, 2007, Rationale, pharmacology and clinical efficacy of partial agonists of alpha4beta2 nACh receptors for smoking cessation, Trends Pharmacol Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clinical efficacy trials show that varenicline reduces smoking urges and withdrawal-related negative affect.

    “These trials document treatment-related reductions in smoking urges and withdrawal-related negative affect (4, 5, 9), as well as reduced smoking reward during a lapse (10).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] Gonzales, 2006, Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: A randomized controlled trial, JAMA source

      Not checked in the free run.

    • cites [5] Jorenby, 2006, Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: A randomized controlled trial, JAMA source

      Not checked in the free run.

    • cites [9] West, 2008, Effect of varenicline and bupropion SR on craving, nicotine withdrawal symptoms, and rewarding effects of smoking during a quit attempt, Psychopharmacology (Berl) source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Depression symptoms are common among smokers and motivate smoking to reduce negative affect.

    “Depression symptoms are common among smokers and motivate smoking to reduce negative affect (44).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Lerman, 1996, Investigation of mechanisms linking depressed mood to nicotine dependence, Addict Behav source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    There were no significant differences in demographic variables by medication order, nor in smoking rate during the two run-up periods (all Ps>.20).

    “There were no significant differences in these variables by medication order, nor were there any differences in smoking rate during the two run up periods (all Ps>.20).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Abstinence during the mandatory phase was biochemically verified with carbon monoxide levels of 10 ppm or less.

    “CO ≤ 10 ppm needed to confirm abstinence on days 11–13”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Statistical models controlled for sex, baseline cigarettes per day, and medication order.

    “All models controlled for sex, cigarettes per day at baseline, and order of medication phases.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    Subjective outcome models included day 10 smoking-as-usual levels as a time-varying covariate, so they tested medication effects on changes from pre-abstinence to abstinence.

    “The models of subjective outcomes also included day 10 (smoking as usual) levels of the measure as a time-varying covariate; thus, these models tested the effect of medication on changes in outcomes from pre-abstinence (day 10) to abstinence (mean of days 11–13).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    The neurocognitive tasks were validated computerized measures of working memory, sustained attention, and executive function.

    “using validated computerized tasks: the Letter-N-back task of working memory (28), the Penn Continuous Performance Task (P-CPT) of sustained attention (29), and the Conditional Exclusion Test (CET) of abstraction in executive function (30, 31).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [28] Ragland, 2002, Working memory for complex figures: An fMRI comparison of letter and fractal n-back tasks, Neuropsychology source

      Not checked in the free run.

    • cites [29] Kurtz, 2001, Comparison of the continuous performance test with and without working memory demands in healthy controls and patients with schizophrenia, Schizophr Res source

      Not checked in the free run.

    • cites [30] Kurtz, 2004, The Penn Conditional Exclusion Test: A new measure of executive-function with alternate forms of repeat administration, Arch Clin Neuropsychol source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    The study used a double-blind, placebo-controlled, within-subject crossover design with counterbalanced medication order.

    “In this placebo-controlled double-blind crossover study, participants completed two 21-day medication periods (varenicline and placebo in counterbalanced order) and a 5–7 day washout period (four participants had longer washout periods due to scheduling issues) (see Figure 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In chronic smokers, nicotine abstinence increases the availability of unbound α4β2 nicotinic acetylcholine receptors, which contributes to abstinence symptoms.

    “In chronic smokers, abstinence from nicotine increases the availability of unbound α4β2 nAChRs, which in turn contributes to abstinence symptoms (35).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Staley, 2006, Human tobacco smokers in early abstinence have higher levels of beta2* nicotinic acetylcholine receptors than nonsmokers, J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Medication adherence was high and did not differ significantly between varenicline and placebo periods (99.27% vs 98.70%, p=.06).

    “Mean adherence levels were 99.27% for the placebo period and 98.70% for the varenicline period (Z = 1.89, p = .06 by Wilcoxon test).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Three participants who did not remain abstinent were excluded from the analyses.

    “Participants who did not remain abstinent (n=3) were excluded.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Varenicline enhances mood and cognitive function during early abstinence from nicotine.

    “Data from the present study indicate that varenicline, a partial agonist at the α4β2 nAChRs, enhances mood and cognitive function during early abstinence from nicotine.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The 5–7 day washout period between the two medication periods was sufficient to eliminate carryover effects of varenicline.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Varenicline might have additional potential benefits for cognitive function beyond those specific to nicotine withdrawal.

    “Prior evidence for the cognitive enhancing effects of selective nAChR agonists suggests further that varenicline might have additional potential benefits in this area beyond those specific to nicotine withdrawal (52).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Mineur, 2007, Cytisine, a partial agonist of high-affinity nicotinic acetylcholine receptors, has antidepressant-like properties in male C57BL/6J mice, Neuropharmacology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The data suggest two novel and potentially important clinical effects of varenicline: enhancement of positive affect and cognitive function.

    “Furthermore, the data suggest two novel and potentially important clinical effects of varenicline, namely enhancement of positive affect and cognitive function.”
    Quote in the paperSubstantial claim
24 of 24

  • The paper relies on this without support.

    The 5–7 day washout period between the two medication periods was sufficient to eliminate carryover effects of varenicline.

    “a 5–7 day washout period (four participants had longer washout periods due to scheduling issues)”

  • The paper relies on this without support.

    The sample of treatment-seeking smokers is representative enough to generalize the study's findings to clinical populations of smokers attempting to quit.

    “To increase the generalizability of results to the clinical setting, we enrolled treatment-seeking smokers (those planning to quit in the next 3 months) (19, 20).”

  • The paper relies on this without support.

    The placebo capsule was indistinguishable from the active medication, so blinding was maintained.

    “The placebo was a sucrose capsule that resembled the active medication (active medication was encapsulated also).”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Consistentz = 3.16reported p = .002 · recomputed p = .002

    “(Z=3.16, p = .002”

  • Consistentz = 1.34reported p = .18 · recomputed p = .180

    “(Z=1.34, p = .18”

  • Consistentz = 1.89reported p = .06 · recomputed p = .059

    “(Z = 1.89, p = .06”

3 of 3

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Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Reference cited before its stated publication date

    Minor

    Reference 22 dates the document to December 2007 but says it was cited on November 16, 2007, before that stated date.

1 of 1

Cites

Flagged first, then by citations

5 of the 60 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Westman, 1992, Smoking while wearing the nicotine patch: Is smoking satisfying or harmful?, Clin Res, 40, 871A

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Related

Authors
Patterson, F., Jepson, C., Strasser, A. A., Loughead, J., Perkins, K. A., Gur, R. C., Frey, J. M., Siegel, S., & Lerman, C.
Affiliations
  • University of Pittsburgh Medical Center (US)
  • University of Pennsylvania (US)
  • Abramson Cancer Center (US)
  • University of Pittsburgh (US)
  • AstraZeneca (United States) (US)
Corresponding author
Lerman, Caryn
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2009-01
Volume
65
Issue
2
Pages
144-149
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2008.08.028
PMC
PMC2615779
OpenAlex
W2070192651
Semantic Scholar
da3580cf90b2994b54327bb9684de9ef3730a592
Cited by
222
References
60
Citations by year
2026: 3 · 2025: 7 · 2024: 5 · 2023: 11 · 2022: 8 · 2021: 1 · 2020: 6 · 2019: 8 · 2018: 9 · 2017: 16 · 2016: 22 · 2015: 9 · 2014: 24 · 2013: 23 · 2012: 19
FWCI
11.32
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Public Health Service (P5084718)
  • National Cancer Institute (P50CA084718)
Topics
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
Keywords
varenicline, nicotine dependence, smoking abstinence, nicotine withdrawal symptoms, smoking urges, mood, cognition, sustained attention, working memory, α4β2 nicotinic acetylcholine receptor, smoking lapse
MeSH terms
Varenicline, Adult, Affect, Attention, Benzazepines, Cognition, Double-Blind Method, Female, Humans, Male, Memory, Short-Term, Middle Aged, Quinoxalines, Reaction Time, Substance Withdrawal Syndrome, Smoking Cessation, Cross-Over Studies, Nicotinic Agonists

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