Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Consensus Article
  • Published:

COMT Val158Met modulates subjective responses to intravenous nicotine and cognitive performance in abstinent smokers

The Pharmacogenomics Journal volume 13, pages 490–497 (2013)Cite this article

Subjects

Abstract

The catechol-O-methyltransferase (COMT) Val158Met polymorphism may be a risk factor for nicotine addiction. This study examined the influence of the COMT Val158Met polymorphism on subjective, physiological and cognitive effects of intravenous (IV) nicotine use in African Americans (AAs; n=56) and European Americans (EAs; n=68) smokers. Overnight abstinent smokers received saline followed by 0.5 and 1.0 mg per 70 kg doses of nicotine, administered 30 min apart. Smokers with valine (Val)/Val genotype, compared with methionine (Met) carriers, had greater negative subjective effects from IV nicotine and had more severe withdrawal severity following overnight abstinence from smoking. Women with Val/Val genotype reported greater difficulty concentrating and irritability than men with Val/Val or Met carrier genotypes. The Val/Val genotype was associated with better performance on the math task and in AA smokers it was associated with greater systolic blood pressure. These results support the rationale of pharmacologically inhibiting COMT to aid with smoking cessation among Val/Val genotype smokers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Slifstein M, Kolachana B, Simpson EH, Tabares P, Cheng B, Duvall M et al. COMT genotype predicts cortical-limbic D1 receptor availability measured with [11C]NNC112 and PET. Mol Psychiatry 2008; 13: 821–827.

    Article  CAS  PubMed  Google Scholar 

  2. Axelrod J, Tomchick R . Enzymatic O-methylation of epinephrine and other catechols. J Biol Chem 1958; 233: 702–705.

    CAS  PubMed  Google Scholar 

  3. Axelrod J . Methylation reactions in the formation and metabolism of catecholamines and other biogenic amines. Pharmacol Rev 1966; 18: 95–113.

    CAS  PubMed  Google Scholar 

  4. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM . Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996; 6: 243–250.

    Article  CAS  Google Scholar 

  5. Weinshilboum RM, Otterness DM, Szumlanski CL . Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Annu Rev Pharmacol Toxicol 1999; 39: 19–52.

    Article  CAS  PubMed  Google Scholar 

  6. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 2001; 98: 6917–6922.

    Article  CAS  PubMed  Google Scholar 

  7. Opmeer EM, Kortekaas R, Aleman A . Depression and the role of genes involved in dopamine metabolism and signalling. Prog Neurobiol 2010; 92: 112–133.

    Article  CAS  PubMed  Google Scholar 

  8. Costas J, Sanjuan J, Ramos-Rios R, Paz E, Agra S, Ivorra JL et al. Heterozygosity at catechol-O-methyltransferase Val158Met and schizophrenia: new data and meta-analysis. J Psychiatr Res 2011; 45: 7–14.

    Article  PubMed  Google Scholar 

  9. Tammimaki AE, Mannisto PT . Are genetic variants of COMT associated with addiction? Pharmacogenet Genomics 2010; 20: 717–741.

    PubMed  Google Scholar 

  10. Hyman SE, Malenka RC, Nestler EJ . Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 2006; 29: 565–598.

    Article  CAS  PubMed  Google Scholar 

  11. Colilla S, Lerman C, Shields PG, Jepson C, Rukstalis M, Berlin J et al. Association of catechol-O-methyltransferase with smoking cessation in two independent studies of women. Pharmacogenet Genomics 2005; 15: 393–398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Munafo MR, Johnstone EC, Guo B, Murphy MF, Aveyard P . Association of COMT Val108/158Met genotype with smoking cessation. Pharmacogenet Genomics 2008; 18: 121–128.

    Article  CAS  PubMed  Google Scholar 

  13. Omidvar M, Stolk L, Uitterlinden AG, Hofman A, Van Duijn CM, Tiemeier H . The effect of catechol-O-methyltransferase Met/Val functional polymorphism on smoking cessation: retrospective and prospective analyses in a cohort study. Pharmacogenet Genomics 2009; 19: 45–51.

    Article  CAS  PubMed  Google Scholar 

  14. David SP, Munafo MR . Genetic variation in the dopamine pathway and smoking cessation. Pharmacogenomics 2008; 9: 1307–1321.

    Article  CAS  PubMed  Google Scholar 

  15. McKinney EF, Walton RT, Yudkin P, Fuller A, Haldar NA, Mant D et al. Association between polymorphisms in dopamine metabolic enzymes and tobacco consumption in smokers. Pharmacogenetics 2000; 10: 483–491.

    Article  CAS  PubMed  Google Scholar 

  16. Loughead J, Wileyto EP, Valdez JN, Sanborn P, Tang K, Strasser AA et al. Effect of abstinence challenge on brain function and cognition in smokers differs by COMT genotype. Mol Psychiatry 2009; 14: 820–826.

    Article  CAS  PubMed  Google Scholar 

  17. Wang Z, Ray R, Faith M, Tang K, Wileyto EP, Detre JA et al. Nicotine abstinence-induced cerebral blood flow changes by genotype. Neurosci Lett 2008; 438: 275–280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Egan MF, Hyde TM, Bonomo JB, Mattay VS, Bigelow LB, Goldberg TE et al. Relative risk of neurological signs in siblings of patients with schizophrenia. Am J Psychiatry 2001; 158: 1827–1834.

    Article  CAS  PubMed  Google Scholar 

  19. Dreher JC, Kohn P, Kolachana B, Weinberger DR, Berman KF . Variation in dopamine genes influences responsivity of the human reward system. Proc Natl Acad Sci USA 2009; 106: 617–622.

    Article  CAS  PubMed  Google Scholar 

  20. Wichers M, Aguilera M, Kenis G, Krabbendam L, Myin-Germeys I, Jacobs N et al. The catechol-O-methyl transferase Val158Met polymorphism and experience of reward in the flow of daily life. Neuropsychopharmacology 2008; 33: 3030–3036.

    Article  CAS  PubMed  Google Scholar 

  21. Htun NC, Miyaki K, Song Y, Ikeda S, Shimbo T, Muramatsu M . Association of the catechol-O-methyl transferase gene Val158Met polymorphism with blood pressure and prevalence of hypertension: interaction with dietary energy intake. Am J Hypertens 2011; 24: 1022–1026.

    Article  CAS  PubMed  Google Scholar 

  22. Sofuoglu M, Yoo S, Hill KP, Mooney M . Self-administration of intravenous nicotine in male and female cigarette smokers. Neuropsychopharmacology 2008; 33: 715–720.

    Article  CAS  PubMed  Google Scholar 

  23. Sofuoglu M, Herman AI, Nadim H, Jatlow P . Rapid nicotine clearance is associated with greater reward and heart rate increases from intravenous nicotine. Neuropsychopharmacology 2012; 37: 1509–1516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. First MB, Spitzer RL, Gibbon M, Williams JBW . Structured Clinical Interview for DSM-IV Axis I Disorders—Patient Edition (SCID-I/P, Version 2.0). Biometrics Research Department, New York State Psychiatric Institute: New York, NY, USA, 1995.

    Google Scholar 

  25. Sofuoglu M, Mouratidis M, Yoo S, Culligan K, Kosten T . Effects of tiagabine in combination with intravenous nicotine in overnight abstinent smokers. Psychopharmacology (Berl) 2005; 181: 504–510.

    Article  CAS  Google Scholar 

  26. Sofuoglu M, Poling J, Mouratidis M, Kosten T . Effects of topiramate in combination with intravenous nicotine in overnight abstinent smokers. Psychopharmacology (Berl) 2006; 184: 645–651.

    Article  CAS  Google Scholar 

  27. Sofuoglu M, Waters AJ, Mooney M, O'Malley SS . Minocycline reduced craving for cigarettes but did not affect smoking or intravenous nicotine responses in humans. Pharmacol Biochem Behav 2009; 92: 135–140.

    Article  CAS  PubMed  Google Scholar 

  28. Benowitz NL, Jacob P, Abijevych KL, Jarvis MJ, Hall S, LeHouezec J et al. Biochemical verification of tobacco use and cessation. Nicotine Tob Res 2002; 4: 149–159.

    Article  Google Scholar 

  29. al'Absi M, Amunrud T, Wittmers LE . Psychophysiological effects of nicotine abstinence and behavioral challenges in habitual smokers. Pharmacol Biochem Behav 2002; 72: 707–716.

    Article  CAS  PubMed  Google Scholar 

  30. Mendelson JH, Sholar MB, Goletiani N, Siegel AJ, Mello NK . Effects of low- and high-nicotine cigarette smoking on mood states and the HPA axis in men. Neuropsychopharmacology 2005; 30: 1751–1763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Newhouse PA, Sunderland T, Narang PK, Mellow AM, Fertig JB, Lawlor BA et al. Neuroendocrine, physiologic, and behavioral responses following intravenous nicotine in nonsmoking healthy volunteers and in patients with Alzheimer's disease. Psychoneuroendocrinology 1990; 15: 471–484.

    Article  CAS  PubMed  Google Scholar 

  32. Pickworth WB, Fant RV . Endocrine effects of nicotine administration, tobacco and other drug withdrawal in humans. Psychoneuroendocrinology 1998; 23: 131–141.

    Article  CAS  PubMed  Google Scholar 

  33. Alexander N, Osinsky R, Mueller E, Schmitz A, Guenthert S, Kuepper Y et al. Genetic variants within the dopaminergic system interact to modulate endocrine stress reactivity and recovery. Behav Brain Res 2011; 216: 53–58.

    Article  CAS  PubMed  Google Scholar 

  34. Wolff K, Tsapakis EM, Pariante CM, Kerwin RW, Forsling ML, Aitchison KJ . Pharmacogenetic studies of change in cortisol on ecstasy (MDMA) consumption. Journal of psychopharmacology (Oxford, England) 2012; 26: 419–428.

    Article  CAS  Google Scholar 

  35. Tiffany ST, Drobes DJ . The development and initial validation of a questionnaire on smoking urges. Br J Addict 1991; 86: 1467–1476.

    Article  CAS  PubMed  Google Scholar 

  36. Cox LS, Tiffany ST, Christen AG . Evaluation of the brief questionnaire of smoking urges (QSU-brief) in laboratory and clinical settings. Nicotine Tobacco Res 2001; 3: 7–16.

    Article  CAS  Google Scholar 

  37. Bell SL, Taylor RC, Singleton EG, Henningfield JE, Heishman SJ . Smoking after nicotine deprivation enhances cognitive performance and decreases tobacco craving in drug abusers. Nicotine Tobacco Res 1999; 1: 45–52.

    Article  CAS  Google Scholar 

  38. Morgan MJ, Davies GM, Willner P . The questionnaire of smoking urges is sensitive to abstinence and exposure to smoking-related cues. Behav Pharmacol 1999; 10: 619–626.

    Article  CAS  PubMed  Google Scholar 

  39. Hughes JR, Hatsukami D . Signs and symptoms of tobacco withdrawal. Arch Gen Psychiatry 1986; 43: 289–294.

    Article  CAS  PubMed  Google Scholar 

  40. Hughes JR, Hatsukami DK . Effects of three doses of transdermal nicotine on post-cessation eating, hunger and weight. J Subst Abuse 1997; 9: 151–159.

    Article  CAS  PubMed  Google Scholar 

  41. Watson D, Clark LA, Tellegen A . Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 1988; 54: 1063–1070.

    Article  CAS  PubMed  Google Scholar 

  42. Reeves D, Kane R, Winter K . Automated Neuropsychological Assessment Metrics (ANAM v3.11a/96) User’s Manual: Clinical and Neurotoxicology Subset. National Cognitive Foundation: San Deigo, CA, USA, 1996 NCRF-SR 96–01.

    Google Scholar 

  43. Snyder FR, Henningfield JE . Effects of nicotine administration following 12 h of tobacco deprivation: assessment on computerized performance tasks. Psychopharmacology (Berl) 1989; 97: 17–22.

    Article  CAS  Google Scholar 

  44. Mancuso G, Warburton DM, Melen M, Sherwood N, Tirelli E . Selective effects of nicotine on attentional processes. Psychopharmacology (Berl) 1999; 146: 199–204.

    Article  CAS  Google Scholar 

  45. Mancuso G, Andres P, Ansseau M, Tirelli E . Effects of nicotine administered via a transdermal delivery system on vigilance: a repeated measure study. Psychopharmacology (Berl) 1999; 142: 18–23.

    Article  CAS  Google Scholar 

  46. Spreen O, Strauss E . A Compendium of Neuropsychological Tests. Spreen O, Strauss E (eds.) Oxford University Press: New York, NY, USA, 1991.

    Google Scholar 

  47. Sofuoglu M, Herman AI, Nadim H, Jatlow P . Rapid nicotine clearance is associated with greater reward and heart rate increases from intravenous nicotine. Neuropsychopharmacology 2012; 37: 1509–1516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Dempsey D, Tutka P, Jacob P, Allen F, Schoedel K, Tyndale RF et al. Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity. Clin Pharmacol Ther 2004; 76: 64–72.

    Article  CAS  PubMed  Google Scholar 

  49. Guo S, Chen da F, Zhou DF, Sun HQ, Wu GY, Haile CN et al. Association of functional catechol O-methyl transferase (COMT) Val108Met polymorphism with smoking severity and age of smoking initiation in Chinese male smokers. Psychopharmacology (Berl) 2007; 190: 449–456.

    Article  CAS  Google Scholar 

  50. Benowitz NL, Hukkanen J, Jacob P . Nicotine chemistry, metabolism, kinetics and biomarkers. Handb Exp Pharmacol 2009; 192: 29–60.

    Article  CAS  Google Scholar 

  51. Pritchard JK, Stephens M, Donnelly P . Inference of population structure using multilocus genotype data. Genetics 2000; 155: 945–959.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Yang BZ, Zhao H, Kranzler HR, Gelernter J . Characterization of a likelihood based method and effects of markers informativeness in evaluation of admixture and population group assignment. BMC Genet 2005; 6: 50.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Domschke K, Baune BT, Havlik L, Stuhrmann A, Suslow T, Kugel H et al. Catechol-O-methyltransferase gene variation: impact on amygdala response to aversive stimuli. Neuroimage 2012; 60: 2222–2229.

    Article  CAS  PubMed  Google Scholar 

  54. Witte AV, Floel A . Effects of COMT polymorphisms on brain function and behavior in health and disease. Brain Res Bull 2012; 88: 418–428.

    Article  CAS  PubMed  Google Scholar 

  55. Bilder RM, Volavka J, Lachman HM, Grace AA . The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes. Neuropsychopharmacology 2004; 29: 1943–1961.

    Article  CAS  PubMed  Google Scholar 

  56. Zhang L, Dong Y, Doyon WM, Dani JA . Withdrawal from chronic nicotine exposure alters dopamine signaling dynamics in the nucleus accumbens. Biol Psychiatry 2012; 71: 184–191.

    Article  CAS  PubMed  Google Scholar 

  57. Stewart SH, Oroszi G, Randall PK, Anton RF . COMT genotype influences the effect of alcohol on blood pressure: results from the COMBINE study. Am J Hypertens 2009; 22: 87–91.

    Article  CAS  PubMed  Google Scholar 

  58. Hagen K, Pettersen E, Stovner LJ, Skorpen F, Holmen J, Zwart JA . High systolic blood pressure is associated with Val/Val genotype in the catechol-o-methyltransferase gene. The Nord-Trondelag Health Study (HUNT). Am J Hypertens 2007; 20: 21–26.

    Article  CAS  PubMed  Google Scholar 

  59. Grim CE, Luft FC, Miller JZ, Meneely GR, Battarbee HD, Hames CG et al. Racial differences in blood pressure in Evans County, Georgia: relationship to sodium and potassium intake and plasma renin activity. J Chronic Dis 1980; 33: 87–94.

    Article  CAS  PubMed  Google Scholar 

  60. Chrysant SG, Danisa K, Kem DC, Dillard BL, Smith WJ, Frohlich ED . Racial differences in pressure, volume and renin interrelationships in essential hypertension. Hypertension 1979; 1: 136–141.

    Article  CAS  PubMed  Google Scholar 

  61. Luft FC, Grim CE, Higgins JT, Weinberger MH . Differences in response to sodium administration in normotensive white and black subjects. J Lab Clin Med 1977; 90: 555–562.

    CAS  PubMed  Google Scholar 

  62. Armani C, Landini L, Leone A . Molecular and biochemical changes of the cardiovascular system due to smoking exposure. Curr Pharm Des 2009; 15: 1038–1053.

    Article  CAS  PubMed  Google Scholar 

  63. Tunbridge EM, Harrison PJ . Importance of the COMT gene for sex differences in brain function and predisposition to psychiatric disorders. Curr Topics Behav Neurosci 2011; 8: 119–140.

    Article  CAS  Google Scholar 

  64. Olsson CA, Anney RJ, Lotfi-Miri M, Byrnes GB, Williamson R, Patton GC . Association between the COMT Val158Met polymorphism and propensity to anxiety in an Australian population-based longitudinal study of adolescent health. Psychiatr Genet 2005; 15: 109–115.

    Article  PubMed  Google Scholar 

  65. Sofuoglu M, Lesage MG . The reinforcement threshold for nicotine as a target for tobacco control. Drug Alcohol Depend 2012; 125: 1–7.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Apud JA, Mattay V, Chen J, Kolachana BS, Callicott JH, Rasetti R et al. Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology 2007; 32: 1011–1020.

    Article  CAS  PubMed  Google Scholar 

  67. Roussos P, Giakoumaki SG, Bitsios P . Tolcapone effects on gating, working memory, and mood interact with the synonymous catechol-O-methyltransferase rs4818c/g polymorphism. Biol Psychiatry 2009; 66: 997–1004.

    Article  CAS  PubMed  Google Scholar 

  68. Shafa R . COMT- inhibitors may be a promising tool in treatment of marijuana addiction trials. A J Addict 2009; 18: 322.

    Google Scholar 

Download references

Acknowledgements

Ann Marie Lacobelle, Greg Kay, Christa Robinson, Michelle Cucinelli, Catherine Aldi, Ellen Mitchell, Lance Barnes and Stacy Minnix provided excellent technical assistance. This research was supported by the Veterans Administration Mental Illness Research, Education and Clinical Center (MIRECC) and NIH grants R03 DA027474, K12 DA00167 (AIH); and R01 DA12690 and R01 DA12849.

Author information

Authors and Affiliations

  1. Department of Psychiatry and VA Connecticut Healthcare System, Yale University, School of Medicine, West Haven, CT, USA

    A I Herman, J Gelernter, J B Listman & M Sofuoglu

  2. Department of Laboratory Medicine, Yale University, School of Medicine, New Haven, CT, USA

    P I Jatlow

Authors
  1. A I Herman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P I Jatlow
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Gelernter
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J B Listman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Sofuoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A I Herman.

Ethics declarations

Competing interests

MS serves as an expert witness on behalf of Pfizer in lawsuits related to varenicline.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Herman, A., Jatlow, P., Gelernter, J. et al. COMT Val158Met modulates subjective responses to intravenous nicotine and cognitive performance in abstinent smokers. Pharmacogenomics J 13, 490–497 (2013). https://doi.org/10.1038/tpj.2013.1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2013.1

Keywords

This article is cited by

Search

Advanced search

Quick links