Ending The Tobacco Holocaust Chapter 7 References and Footnotes:

Ending The Tobacco Holocaust: how Big Tobacco affects our health, pocketbook and political freedom, and what we can do about it.

Chapter 7: The Biology of Tobacco Addiction.

1 “Adults puff away knowing habit can kill,” Reuters Health. February 2004.

2 http://tobaccodocuments.org/tplp/566628841-8854.html
and
http://tobaccodocuments.org/bliley_bw/566628841-8854.html.

3 Daley class action lawsuit in Chicago. (IL complaint p. 32). Also in Montana lawsuit. Joseph P. Mazurek Attorney General, Chris Tweeten, Chief Deputy Attorney General.

4 Blue Cross/Blue Shield of NJ v. Philip Morris - Complaint United States District Court Eastern District of New York. May 3, 2002.

5 Kandel, Denise and Chen, Kevin, Nicotine and Tobacco Research. September 2000.

6 “Nicotine most likely to hook women, whites and young,” Reuters Health. September 2000.

7 Psychologist Kenneth A. Perkins, Ph.D., and colleagues from the University of Pittsburgh School of Medicine and the Children’s Hospital of Pittsburgh in Pennsylvania. Experimental and Clinical Psychopharmacology, 2000;8:462472.

8“Initial Sensitivity to Nicotine May Put Sensation Seekers at Higher Risk of Becoming Smokers.” Experimental and Clinical Psychopharmacology/MedscapeWire. Nov. 21, 2000.

9 Judith, S., Yongue, M.D., Journal of the American Medical Association. 1999;281:2145–2146.

10 Mestel, Rosie, “Mentally Ill Twice As Likely To Be Smokers, Study Finds; Tobacco: Special Programs May Be Needed To Encourage Patients To Quit, Given Their Isolation and Tendency To Use Nicotine To Fight Depression, Experts Say.” Los Angeles Times Nov. 22, 2000.

11 Peto, R., Lopez, A. D., Boreham, J. et al., “Mortality from tobacco in developed countries: indirect estimation from national vital statistics.” Lancet, 1992; 339: 1268–78.

12 George, T. P., Vessicchio, J. C., “Nicotine addiction and other psychiatric disorders.” Psychiatric Times, 2001; 17(2): online edition and George, T. P., Vessicchio, J. C. “Nicotine addiction and schizophrenia. Psychiatric Times. 2001; (2): 39–42.

13 The figure is used in Kalman, D., Morissette, S. B., George, T. P. “Co-Morbidity of Smoking in Patients with Psychiatric and Substance Use Disorders.” The American Journal on Addictions, 14:106–123. Please see that excellent paper for more information on the topic.

14 Lasser, K., Boyd, J. W., Woolhandler, S. et al., “Smoking and mental illness: a population-based prevalence study.” Journal of the American Medical Association, 2000; 284(20): 2606–2610.

15 Kirch, D. G., Nicotine and Major Mental Disorders. In Nicotine In Psychiatry, edited by Piasecki, M., and Newhouse, P. A. Washington, D.C, American Psychiatric Press, 2000, pp. 111–130.

16 Peto, R., Lopez, A. D,, Boreham, J. et al., “Mortality from tobacco in developed countries: indirect estimation from national vital statistics.” Lancet, 1992; 339: 1268–78.

17 Hughes, J. R., Hatsukami, D. K., Mitchell, J. E., Dahlgren, L. A., “Prevalence of smoking among psychiatric outpatients. American Journal of Psychiatry, 1986, 143(8): 993–997.

18 George, T. P., Krystal, J. H., “Co-morbidity of psychiatric and substance abuse disorders.” Current Opinion in Psychiatry, 2000; 13(3):327–331.

19 Lasser, K., Boyd, J. W., Woolhandler, S. et al., “Smoking and mental illness: a population-based prevalence study.” Journal of the American Medical Association, 2000; 284(20): 2606–2610.

20 Hughes, J. R., Hatsukami, D. K., Mitchell, J. E., Dahlgren, L. A., “Prevalence of smoking among psychiatric outpatients.” American Journal of Psychiatry, 1986, 143(8): 993–997.

21 George, T. P., Vessicchio, J. C., “Nicotine addiction and other psychiatric disorders.” Psychiatric Times, 2001; 17(2): online edition and George, T. P., Vessicchio, J. C. “Nicotine addiction and schizophrenia. Psychiatric Times. 2001; (2): 39–42.

22 Lasser, K., Boyd, J. W., Woolhandler, S. et al., “Smoking and mental illness: a population-based prevalence study.” Journal of the American Medical Association, 2000; 284(20): 2606–2610.

23 Amerling, M., Bankier, B., Berger, P. et al., “Panic disorder and cigarette smoking behavior.” Comprehensive Psychiatry, 1999; 40(1): 35–38.

24 Lasser, K., Boyd, J. W., Woolhandler, S. et al., “Smoking and mental illness: a population-based prevalence study.” Journal of the American Medical Association, 2000; 284(20): 2606–2610.

25 George, T. P., Vessicchio, J. C., “Nicotine addiction and other psychiatric disorders.” Psychiatric Times, 2001; 17(2): online edition and George, T. P., Vessicchio, J. C. “Nicotine addiction and schizophrenia. Psychiatric Times. 2001; (2): 39–42.

26 Lasser, K., Boyd, J. W., Woolhandler, S. et al., “Smoking and mental illness: a population-based prevalence study.” Journal of the American Medical Association, 2000; 284(20): 2606–2610.

27 Kirch, D. G., Nicotine and Major Mental Disorders. In Nicotine In Psychiatry, edited by Piasecki, M., and Newhouse, P. A. Washington, D.C, American Psychiatric Press, 2000, pp. 111–130.

28 Breese, Leonard S., Adams, C., et al., “Smoking and schizophrenia: abnormal nicotinic receptor expression.” European Journal of Pharmacology, 2000; 393(1-3):237–42. Leonard et al. showed that the chromosomal locus of the human alpha-7 gene (15q14) was linked to the gating deficit with a lod of 5.3, and antagonists of the alpha-7 receptor (such as alpha-bungarotoxin and methyllycaconitine) induced a loss of gating in rodents. They cloned the human alpha-7 gene and found it to be partially duplicated proximal to the full-length gene. The duplication was expressed in both the brain and in peripheral blood cells of normal subjects, but was missing in some schizophrenic subjects.

29 Freedman, R., Coon, H., Myles-Worsley, M., et al., “Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus.” Proceedings of the National Academy of Sciences Online, U S A 1997; 94(2):587–92. Freedman et al., utilizing a genome-wide linkage analysis, and assuming autosomal dominant transmission, showed that the defect was linked [maximum logarithm of the odds (lod) score = 5.3 with zero recombination] to a dinucleotide polymorphism at chromosome 15q13-14, the site of the alpha 7-nicotinic receptor. They also noted that despite many schizophrenics' extremely heavy nicotine use, nicotinic receptors were not previously thought to be involved in schizophrenia.

30 Neves-Pereira, M., Bassett, A. S., Honer, W. G., et al., “No evidence for linkage of the CHRNA7 gene region in Canadian schizophrenia families.” American Journal of Medical Genetics, 1998; 81 (5): 361–363. Neves-Pereira et al. 11 genotyped 5 schizophrenia families with a total of 96 subjects, and they weren’t able to replicate the involvement of the alpha 7-nicotinic receptor gene in the cases of schizophrenia that they investigated.

31 Nakajima, M., Yamagishi, S., Yamamoto, H., et al., “Deficient cotinine formation from nicotine is attributed to the whole deletion of the CYP2A6 gene in humans.” International Journal of Clinical Pharmacology and Therapeutics, 2000; 67(1):57–69.

32 Callaghan, J. T., Bergstrom, R. F., Ptak, L. R., Beasley, C. M., Olanzapine. Pharmacokinetic and pharmacodynamic profile. Clinical Pharmacokinetics. 1999; 37(3):177-93.

33 Benowitz [34] noted that cigarette smoking increases the metabolism of imipramine, one of the metabolites of diazepam, but not diazepam, nortripyline or lorazepam. Perry et al. [35] developed different dosing equations for haloperidol for smokers. At the lower end of the desired therapeutic range smokers may require as much as sevenfold higher doses than nonsmokers, while in the upper limit of the therapeutic range, smokers may still require twice the dosing of that for nonsmokers.
     Ereshefsky et al. [36] has noted that smoking, including passive inhalation affects plasma drug clearance of many antipsychotics. Cigarette smokers on average have a 25% to 50% faster metabolic rate for thiothixene than nonsmokers, while the data for fluphenazine, both as oral and depot formulations, demonstrated a nearly 100% increase in clearance rates. They also noted that haloperidol clearance is also increased by 50% or more, and pointed out that there is about a 50% decrease in the half-life of olanzepine observed for smoking versus non-smoking patients of the same gender. Alternatively, they noted that if a patient ceases smoking while maintaining a constant dose of antipsychotic medication, that increased adverse events could occur.
     Two studies have demonstrated an interesting finding, that patients being treated with clozapine have a significant decrease in daily cigarette use as compared to those on standard neuroleptics. [37, 38]
     While numerous studies have attempted to investigate the relationship between smoking behavior and occurrence of EPS, results have often been contradictory, though there may be a potential tendency for increased tardive dyskinesia, and a decrease in parkinsonism among smokers.39 Further study needs to occur regarding those issues.

34 Benowitz, N. L., “Pharmacologic aspects of cigarette smoking and nicotine addiction.” New England Journal of Medicine. 1988; 319: 1318–1330.

35 Perry, P. J., Miller, D. D., Arndt, Sv, et al., “Haloperidol dosing requirements: the contribution of smoking and nonlinear pharmacokinetics.” Journal of Clinical Psychopharmacology, 1993; 13: 46–51.

36 Ereshefsky, L., Riesenman, C., Lam, Y. W., “Serotonin selective reuptake inhibitor drug interactions and the cytochrome P450 system.” Journal of Clinical Psychiatry, 1996; 57(Suppl 8): 17–24.

37 George, T. P., Sernyak, M. J., Ziedonis, D. M., et al., “Effects of clozapine on smoking in chronic schizophrenic outpatients.” Journal of Clinical Psychiatry, 1995; 56: 344–346.

38 McEvoy, J. P., Freudenreich, O., McGee, M., et al., “Clozapine decreases smoking in patients with chronic schizophrenia.” Biological Psychiatry, 1995; 37: 550–552. 39 Kirch, D. G., Nicotine and Major Mental Disorders. In Nicotine In Psychiatry, edited by Piasecki, M., and Newhouse, P. A. Washington, D.C, American Psychiatric Press, 2000, pp. 111–130.

40 Ibid.

41 Breslau, N., Kilbey, M. M., Andreski, P., “Nicotine dependence and major depression.” Archives of General Psychiatry, 1993; 50: 31-35.

42 George, T. P., Krystal, J. H., “Co-morbidity of psychiatric and substance abuse disorders.” Current Opinion in Psychiatry, 2000; 13(3):327–331.

43 Piasecki, M., “Smoking, nicotine and mood.” In Nicotine In Psychiatry, edited by Piasecki, M., and Newhouse, P. A., Washington, D.C., American Psychiatric Press, 2000, pp.131–147.

44 Hughes, J. R., Clonidine, depression and smoking cessation. Journal of the American Medical Association, 1988; 254: 2901–2.

45 Kendler, K. S., Neale, M. C., MacLean, C. J., et al., Smoking and major depression: a causal analysis. Archives of General Psychiatry, 1993; 50: 36–43.

46 Fergusson, D. M., Lynskey, M. T., Horwood, L. J. “Co-morbidity between depressive disorders and nicotine dependence in a cohort of 16-year-olds.” Archives of General Psychiatry, 1996; 53: 1043–1047.

47 Goodman, E., Capitman, J., Depressive Symptoms and Cigarette Smoking Among Teens. Pediatrics 2000, 106(4): 748–755.

48 Wu, L-T, Anthony, J. C. “Tobacco smoking and depressed mood in late childhood and early adolescence.” American Journal of Public Health, 1999; 89(12): 1837–1840.

49 Johnson, J. G., Cohen, P., Pine, D., et al., “Association between cigarette smoking and anxiety disorders during adolescence and early adulthood.” Journal of the American Medical Association, 2000; 284(18): 2348–2351.

50 Ibid.

51 Breslau, N., Klein, D. F. , “Smoking and panic attacks: an epidemiologic investigation.” Archives of General Psychiatry, 1999; 56(12): 1141–1147.

52 Amerling, M., Bankier, B., Berger, P., et al., “Panic disorder and cigarette smoking behavior.” Comprehensive Psychiatry, 1999; 40(1): 35–38.

53 Lasser, K., Boyd, J. W., Woolhandler, S. et al., “Smoking and mental illness: a population-based prevalence study.” Journal of the American Medical Association, 2000; 284(20): 2606–2610.

54 Nordine, R. Segmentation study: overview. Available at: http://galen.library.ucsf.edu/tobacco/mangini/html/c/039/otherpages/index.html; 9-10. Accessibility verified Oct. 3, 2000.

55 “Nicotine’s brain actions linked to reward pathways,” http://www.bcm.edu/pa/nicotine_reward.htm. Nov. 26, 1997.

56 Di Chiara, F., Imperato, A., “Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.” Proceedings of the National Academy of Science U S A. July 1988;85(14):5274–8.

57 “Nicotine’s brain actions linked to reward pathways,” http://www.bcm.edu/pa/nicotine_reward.htm. Nov. 26, 1997.

58 George, Tony P., M.D., and Vessicchio, Jennifer C., M..S.W., Nicotine Addiction and Schizophrenia. Psychiatric Times. Vol. XVII, Issue 2.

59 Nestler, E. J. Is there a common molecular pathway for addiction? Nature Neuroscience. 8, 1445–1449.

60 Drugs of abuse, despite diverse initial actions, produce some common effects on the VTA and NAc. Stimulants directly increase dopaminergic transmission in the NAc. Opiates do the same indirectly: they inhibit GABAergic interneurons in the VTA, which disinhibits VTA dopamine neurons. Opiates also directly act on opioid receptors on NAc neurons, and opioid receptors, like D2 dopamine (DA) receptors, signal via Gi; hence, the two mechanisms converge within some NAc neurons. The actions of the other drugs remain more conjectural. Nicotine seems to activate VTA dopamine neurons directly via stimulation of nicotinic cholinergic receptors on those neurons and indirectly via stimulation of its receptors on glutamatergic nerve terminals that innervate the dopamine cells. Alcohol, by promoting GABAA receptor function, may inhibit GABAergic terminals in VTA and hence disinhibit VTA dopamine neurons. It may similarly inhibit glutamatergic terminals that innervate NAc neurons. Many additional mechanisms (not shown) are proposed for alcohol. Cannabinoid mechanisms seem complex, and they involve activation of CB1 receptors (which, like D2 and opioid receptors, are Gi linked) on glutamatergic and GABAergic nerve terminals in the NAc, and on NAc neurons themselves. Phencyclidine (PCP) may act by inhibiting postsynaptic NMDA glutamate receptors in the NAc. Finally, there is some evidence that nicotine and alcohol may activate endogenous opioid pathways and that these and other drugs of abuse (such as opiates) may activate endogenous cannabinoid pathways (not shown). PPT/LDT, peduncular pontine tegmentum/lateral dorsal tegmentum. Also see: Nestler, E. J., Malenka, R. C., Scientific American, pp 78–85, March 2004.

61 “Nicotine’s brain actions linked to reward pathways,” http://www.bcm.edu/pa/nicotine_reward.htm. Nov. 26, 1997.

62 Fowler, J. S., Volkow, N. D., Wang, G-J., Pappas, N., et al., Nature 379, pp. 733–736, Feb. 2, 1996.

63 Fowler, J. S., Volkow, N. D., Wang, G-J., Pappas, N., et al., Proceedings of the National Academy of Sciences 93, pp. 14065–14069, November 1996.

64 Fowler, J. S., Logan, J., Wang, G-J., Volkow, N. D., et al., Proceedings of the National Academy of Sciences, 100(20), pp. 11600–11605, Sept. 30, 2003.

65 Fowler, J. S., Volkow, N. D., Wang, G-J., Pappas, N., et al., Nature 379, pp. 733–736, Feb. 2, 1996.

66 Fowler, J. S., Volkow, N. D., Wang, G-J., Pappas, N., et al., Proceedings of the National Academy of Sciences 93, pp. 14065–14069, November 1996.

67 Robinson, J. D., Cinciripini, P. M., “The effects of stress and smoking on catecholaminergic and cardiovascular response.” Behavioral Medicine, 2006 (Spring); 32(1): 13–18.

68 This figure is provided by the National Institute of Drug Abuse. It comes from A collection of NIDA Notes: Research on Nicotine. NN0031. p. 6.

69 Robinson, J. D., Cinciripini, P. M., “The effects of stress and smoking on catecholaminergic and cardiovascular response.” Behavioral Medicine, 2006 (Spring); 32(1): 13–18.

70 Anthony, J. C., Warner, L. A., Kessler, R. C. (1994), Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National Comorbidity Survey. Experimental and Clinical Psychopharmacology, 2(3):244–268.

71 McLellan, A. T., Lewis, D. C., O’Brien, C. P., Kleber, H. D. (2000). “Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation.” Journal of the American Medical Association 284(13):1689–1695.

72 Hunt, W. A., Barnett, L. W., Branch, L. G., “Relapse rates in addiction programs.” Journal of Clinical Psychology. October 1971;27(4):455–6.

73 Ibid.

74 Adriani, W., et al., Journal of Neuroscience, 23(11), pp. 4712–4716, June 1, 2003.

75 Ibid.

76 Noble EP, St. Joer ST, Ritchie T, et. al. D2 dopamine receptor gene and cigarette smoking: a reward gene? Medical Hypotheses 1994; 42: 257-60.

77 Blum, K., Braverman, E. R., Holder, J. M., Lubar, J. F., Monastra, V. J., Miller, D., Lubar, J. O., Chen, T. J., Comings, D. E., Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. Journal of Psychoactive Drugs. November 2000;32 Suppl:i-iv, 1–112.

78 Comings, D. E.,, Blum, K., “Reward deficiency syndrome: genetic aspects of behavioral disorders. Progress in Brain Research. 2000;126:325–41.

79 Blum, K., Sheridan, P. J., Wood, R. C., Braverman, E. R., Chen, T. J., Comings, D. E., “Dopamine D2 receptor gene variants: association and linkage studies in impulsive-addictive-compulsive behaviour. Pharamcogenetics. June 1995;5(3):121–41.

80 Blum, K., Sheridan, P. J., Wood, R. C., Braverman, E. R., Chen, T. J., Cull, J. G., Comings, D. E., “The D2 dopamine receptor gene as a determinant of reward deficiency syndrome.” Journal of the Royal Society of Medicine. July 1996;89(7):396–400.

81 Given the complexity of the issue, only a brief discussion of possible genetic factors that might be involved nicotine addiction, and the co-morbidity of nicotine addiction and other substance abuse will be discussed here. It has been hypothesized that the positive reinforcement effects of nicotine are manifested through activation of the mesolimbic dopaminergic reward pathways of the brain. [82, 83] A substantial body of evidence indicates that activation of nicotinic receptors by nicotine enhances dopamine release in the brain, especially in the nucleus accumbens and the ventral tegmental area, regions known to be involved in reward mechanisms. [84, 85] Accumulating evidence points to the involvement of the dopaminergic system in the reinforcing actions, which are implicated in the addictive properties of nicotine and several other psychoactive agents. [86, 87]
     While the genetic basis of nicotine addiction isn’t clearly understood, and is likely polygenic in nature, numerous researchers have suggested a role for several dopamine receptor polymorphisms. Noble et al. have shown that the A1 allele of the DRD2 gene leads to decreased numbers of normally functioning D2 receptors in the brain [88, 89]: the binding affinity (Kd) was found to be similar between A1+ (A1A1 or A1A2) and A1- (A2A2) allele subjects, but the number of binding sites (Bmax) decreased by 30% in subjects carrying the A1+ allele. In vivo studies have also shown a reduced number of dopamine D2 receptors in the brains of subjects who carry the A1+ allele, compared with those who lack that allele. [90, 91] In addition, a positron emission tomography study has shown that there is diminished glucose metabolism in the limbic areas of the brain of A1+ allele subjects when compared with those who lack that allele. [92]
     Various researchers have observed that the age of onset of smoking in smokers was significantly younger in subjects who carried the minor A1+ (A1A1 or A1A2 genotype) or B1+ (B1B1 or B1B2 genotype) of the DRD2 gene allele than in those with only the major A1- (A2A2 genotype) or B1- (B2B2 genotype) allele, respectively. [93, 94]
     Significantly fewer attempts to quit were made by ever smokers and current smokers carrying the A1+ allele than by those who do not carry this allele. [95, 96] Studies by Noble et al. [97], and Comings et al. [98] have noted increased difficulty with smoking cessation in patients who have the DRD2 A1+ allele, as compared to those with the A1- allele.
     Some research also suggests that increased difficulty in smoking cessation may be related to other dopamine receptor gene alleles, including the presence of dopamine receptors DRD2 B1+ allele, and DRD4 7 repeat alleles (which may modulate the association between depression and self-medication smoking [99]).      Caskey et al. have noted a decrease in smoking behavior in patients treated with the D2 dopamine agonist bromocriptine. [100] It has been hypothesized that the DRD2 is a reinforcement gene, and that subjects with the A1+ or B1+ allele may compensate for an inherent deficiency in their dopaminergic system by using nicotine, alcohol and other substances that are known to increase dopamine levels in the brain. [101, 102] It has further been hypothesized that subsequent stimulation of the A1+ or B1+ allele subjects’ fewer D2 receptors could provide enhanced reward and pleasure; for these reasons individuals continue to use nicotine and other substances, which subsequently leads to medical and dother complications.
     Thus, polymorphisms of the DRD2 and DRD4 may be important, though non-specific, etiological factors involved with the high rate of comorbidity found in patients who have both nicotine addiction and who also abuse or are dependent on various illicit substances.]
     Dr. Munafo’s research team’s systemic review [103] of candidate gene studies indicated effects of the DRD2 Taq1A polymorphism and smoking initiation, the 5HTT LPR and CYP2A6 reduced-activity polymorphisms and smoking cessation, and the DRD2 Taq1A and CYP2A6 reduced-activity polymorphisms and cigarette consumption. The evidence for an effect of specific genes was modest, however, and evidence indicated substantial between-study heterogeneity in most cases, with the exception of the effects of the 5HTT and CYP2A6 genes on smoking cessation. When a random-effects model was applied to analyses in which evidence indicated significant heterogeneity, the effects were in all cases no longer statistically significant. They concluded that evidence for a contribution of specific genes to smoking behavior remains modest.
     Various studies have pointed to different loci in the genome for candidate genes. According to a research group led by Dr. Straub [104], there are genes on six chromosomes—2, 4, 10, 16 17, and 18—that may be linked to nicotine dependence. (However, those results weren’t replicated by another research team [105]). According to the report in Molecular Psychiatry, finding the genes linked to tobacco addiction could lead to “'earlier identification of individuals at risk, and development of more effective methods for helping people to quit smoking.” The researchers used a genome scan to detect the genes that could increase the risk of nicotine addiction. (The association they found between these genes and nicotine dependence may be “due to chance,” but the results definitely warrant further study.) [106] Dr. Ming Li’s research team found significant linkage of smoking quantity to chromosome 11, and suggestive linkage to chromosomes 4, 5, 9, 14, and 17. [107] In brief summary, researchers think that nicotine addiction is a genetically complex trait that also involves elements of personality, environment, and psychopathology. [108] For further reading, please see references 109, 111, 112, and 116.

82 Wise, R. A., Rompre, P. P., “Brain dopamine and reward.” Annual Review of Psychology. 1989; 40:191–225.

83 Koob, G. F.,”Drugs of abuse: anatomy, pharmacology and function of reward pathways.” Trends in Pharmacological Sciences. 1992; 13: 177–184.

84 Brazell, M. P., Mitchell, S. N., Joseph, M. H., Gray, J. A., Acute administration of nicotine increases the invitro extracellular levels of dopamine, 3,4 dihydroxyphenylacetic acid and ascorbic acid preferentially in the nucleus accumbens of the rat: comparison with caudate-putamen. Neuropharmacology. 1990; 29: 1177–1185.

85 Pontieri, F. E., Tanda, G., Orzi, F., Di Chiara, G., Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 1996; 382: 255–7.

86 Wise, R. A., Rompro, P. P., “Brain dopamine and reward. Annual Review of Psychology. 1989; 40:191–225

87 Koob, G. F., ”Drugs of abuse: anatomy, pharmacology and function of reward pathways.” Trends in Pharmacological Science. 1992; 13: 177–184.

88 Noble, E. P., “The gene that rewards alcoholism. Scientific American Science and Medicine. 1996 March/April: 52–61.

89 Noble, E. P., Blum, K., Ritchie, T., et al., “Allelic association of the D2 dopamine receptor gene with receptor binding characteristics in alcoholism.” Archives of General Psychiatry. 1991, 48: 648–654.

90 Pohjalainen, T., Rinne, J., Nagren, K., et. al., “Genetic determinants of human D2 dopamine receptor binding characteristics in vivo.” American Journal of Human Genetics. 1996; 59(4 suppl): A387.

91 Jonsson, E. G., Nothen, M. M., Grunhage, F., et al., “Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal receptor density of health volunteers.” Molecular Psychiatry. 1999; 4: 290–296.

92 Noble, E. P., Gottschalk, L. A., Fallon, J. H., Ritchie, T. L., Wu, J. C., “D2 dopamine polymorphism and brain regional glucose metabolism.” American Journal of Human Genetics. 1997; 74: 162–6.

93 Spitz, M. R., Shi, H., Yang, F., Hudmon, S., Jiang, H., Chamberlain, R. M., Amos, C. I., Wan, Y., Cinciripini, P., Hong, W. K., Wu, X., “Case-control study of the D2 dopamine receptor gene and smoking status in the lung cancer patients.” Journal of the National Cancer Institute. 1998; 90(5): 358–363.

94 Comings, D. E., Ferry, L., Bradshaw-Robinson, S., et al., “The dopamine D2 receptor (DRD2) gene: a genetic risk factor in smoking.” Pharmacogenetics. 1996; 6: 73–9.

95 Spitz, M. R., Shi, H., Yang, F., Hudmon, S., Jiang, H., Chamberlain, R. M., Amos, C. I., Wan, Y., Cinciripini, P., Hong, W. K., Wu, X., “Case-control study of the D2 dopamine receptor gene and smoking status in the lung cancer patients.” Journal of the National Cancer Institute. 1998; 90(5): 358–363.96 Noble, E. P., “The DRD2 gene, smoking, and lung cancer.” Journal of the National Cancer Institute. 1998; 90(5): 343–345.

97 Noble, E. P., St. Joer, S. T., Ritchie, T., et al., “D2 dopamine receptor gene and cigarette smoking: a reward gene?” Medical Hypotheses. 1994; 42: 257–60.

98 Comings, D. E., Ferry, L., Bradshaw-Robinson, S., et al. “The dopamine D2 receptor (DRD2) gene: a genetic risk factor in smoking.” Pharmacogenetics. 1996; 6: 73–9.

99 Lerman, C., Caporaso, N., Main, D., Audrain, J., Boyd, N. R., Bowman, E. D., and Shields, N. R., “Depression and self-medication with nicotine: the modifying influence of the dopamine D4 receptor gene.” Health Psychology. 1998; 17(1): 56–62.

100 Caskey, N. H., Jarvik, M. E., Wirsching, W. C., “The effects of dopaminergic D2 stimulation and blockade on smoking behavior.” Experimental and Clinical Psychopharmacology. 1999; 7: 72–78.

101 Jonsson, E. G., Nothen, M. M., Grunhage, F. et al., “Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal receptor density of health volunteers.” Molecular Psychiatry. 1999; 4: 290–296.

102 Noble, E. P., “The DRD2 gene, smoking, and lung cancer.” Journal of the National Cancer Institute. 1998; 90(5): 343–345.

103 Munafo, M., Clark, T., Johnstone, E., Murphy, M., Walton, R. “The genetic basis for smoking behavior: a systematic review and meta-analysis.” Nicotine & Tobacco Research. August 2004;6(4):583–97.

104 Straub, R. E., Sullivan, P. F., Ma, Y., Myakishev, M. V., Harris-Kerr, C., Wormley, B., Kadambi, B., Sadek, H., Silverman, M. A., Webb, B. T., Neale, M. C., Bulik, C. M., Joyce, P. R., and Kendler, K. S., “Susceptibility genes for nicotine dependence: a genome scan and followup in an indpendent sample suggest that regions on chromosomes 2, 4, 10, 17, and 18 merit further study.” Molecular Psychiatry. 199;4:12–144.

105 Li, M. D., The genetics of smoking related behavior: a brief review. American Journal of Medical Science. October 2003;326(4):168–73.

106 Straub, R. E., Sullivan, P. F., Ma, Y., Myakishev, M. V., Harris-Kerr, C., Wormley, B., Kadambi, B., Sadek, H., Silverman, M. A., Webb, B. T., Neale, M. C., Bulik, C. M., Joyce, P. R., and Kendler, K. S., “Susceptibility genes for nicotine dependence: a genome scan and followup in an indpendent sample suggest that regions on chromosomes 2, 4, 10, 17, and 18 merit further study.” Molecular Psychiatry. 199;4:12–144.

107 Li, M. D., “The genetics of smoking related behavior: a brief review. American Journal of Medical Science. October 2003;326(4):168–73.

108 Straub, R. E., Sullivan, P. F., Ma, Y., Myakishev, M. V., Harris-Kerr, C., Wormley, B., Kadambi, B., Sadek, H., Silverman, M. A., Webb, B. T., Neale, M. C., Bulik, C. M., Joyce, P. R., and Kendler, K. S., “Susceptibility genes for nicotine dependence: a genome scan and followup in an indpendent sample suggest that regions on chromosomes 2, 4, 10, 17, and 18 merit further study.” Molecular Psychiatry. 199;4:12–144.

109 Li, M. D., “The genetics of smoking related behavior: a brief review. American Journal of Medical Science. October 2003;326(4):168–73.

110 Other reviews have stated that “the heritability estimates for smoking in twin studies have ranged from 46 to 84%,111 and “as much as 70% of the variance in the transmission to nicotine dependence is thought to be genetically medicated, with very small effects of shared environment.”

111 Batra, V., Patkar, A. A., Berrettini, W. H., Weinstein, S. P., Leone, F. T., “The genetic determinants of smoking.” Chest. 2003 May;123(5):1730–9.

112 Lerman, C., Berrettini, W., “Elucidating the role of genetic factors in smoking behavior and nicotine dependence.” Am J Med Genet B Neuropsychiatr Genet. April 1, 2003;118(1):48–54.

113 This figure is provided by the National Institute of Drug Abuse. It comes from A Collection of NIDA Notes: Research on Nicotine. NN0031. p. 56.

114 Li, M. D., “The genetics of smoking related behavior: a brief review.” American Journal of Medical Science. October 2003;326(4):168–73.

115 Batra, V., Patkar, A. A., Berrettini, W. H., Weinstein, S. P., Leone, F. T., “The genetic determinants of smoking.” Chest. 2003 May;123(5):1730–9.

116 Munafo, M., Clark, T., Johnstone, E., Murphy, M., Walton, R., “The genetic basis for smoking behavior: a systematic review and meta-analysis.” Nicotine & Tobacco Research. Aug. 6, 2004;6(4):583–97.

117 Brody, A., Mandelkern, M., Olmstead, R., Scheibel, D., Hahn, E., Shiraga, S., Zamora-Paja, E., Farahl, J., Saxena, S., London, E., McCracken, J., “Gene variants of brain dopamine pathways and smoking-induced dopamine release in the ventral caudate/nucleus accumbens.” Archives of General Psychiatry. 2006; 63: 808–816.Permission for the use of the figure granted by the Archives of General Psychiatry.

118 Personal communication with Dr. Ernest Noble at UCLA.

119 Fraga, M. F., et al., Epigenetic differences arise during the lifetime of monozygotic twins. Proceedings of the National Academy of Sciences U S A. July 26, 2005;102(30):10604-9. Epub July 11, 2005.

120 Roy-Byrne, P., Emerging perspectives: Epigenesis – how experience sculpts genes. Journal Watch Psychiatry 2005 1(9): 69–70.

121 Ibid.

122 Fraga, M. F., et al., “Epigenetic differences arise during the lifetime of monozygotic twins. Proceedings of the National Academy of Sciences U S A. July 26, 2005;102(30):10604-9. Epub July 11, 2005.

123 Roy-Byrne, P., “Emerging perspectives: Epigenesis – how experience sculpts genes.” Journal Watch Psychiatry. 2005 1(9): 69–70.

124 Ibid.

125 Martin, G. M., Epigenetic drift in aging identical twins. Proc Natl Acad Sci U S A 2005 Jul 26;102(30):10413-4. Epub July 18, 2005.

126 Roy-Byrne, P., “Emerging perspectives: Epigenesis – how experience sculpts genes. Journal Watch Psychiatry. 2005 1(9): 69–70.