Health  Vol.6 No.16 , September 2014
Hypothesizing “Reward” Gene Polymorphisms May Predict High Rates of Injury and Addiction in the Workforce: A Nutrient and Electrotherapeutic Based Solution
ABSTRACT
We hypothesize that individuals with genetic predisposition to Substance Use Disorder (SUD) may have greater likelihood of experiencing work related accidents. We further hypothesize that high risk populations will carry single or multiple polymorphisms associated with brain reward circuitry and/or brain reward cascade, including: Dopaminergic (i.e. DRD2 receptor genes); Serotonergic (i.e. 5-HTT2 receptor genes); Endorphinergic (i.e. pre-enkephalin genes); Gabergic (i.e. GABAA receptor genes); Neurotransmitter Metabolizing genes (i.e. MAO and COMT genes) among others (GARSRXTM). Analgesic addiction as well as “pseudoaddiction” must be treated to improve pain control and its management. We propose that non-pharmacological alternatives to pain relief, in high risk, addiction-prone individuals, are Electrotherapeutic Device(s) and Programs. We further propose patented KB220Z, a nutraceutical designed to release dopamine at the nucleus accumbens, will reduce craving behavior, in genetically programmed individuals. By utilizing both alternatives in DNA analyzed injured workers, a reduction in analgesic addiction (genuine or pseudo) leads to improved health and quicker return to work. We also hypothesize that this novel approach will impact costs related to injuries in the workforce. Effective management of chronic pain, especially in high addiction-prone workforce populations, is possible in spite of being particularly elusive. A series of factors encumber pain assessment and management, including analgesia addiction, pharmacogenomic response to pain medications, and genetically inherited factors involving gene polymorphisms. Additional research is required to test these stipulated hypotheses related to genetic proneness to addiction, but also proneness to accidents in the workplace and reduction of craving behavior. Our hypothesis that genotyping coupled with both KB220ZTM and the pharmaceutical-free Electrotherapy, will reduce iatrogenic induced analgesia addiction. This approach will achieve attainable effective pain management and quicker return to work. We propose outcomes such as the Reward Deficiency System SolutionTM may become an adjunct in the war against iatrogenic pain medication addiction.

Cite this paper
Blum, K. , Simpaatico, T. , Waite, R. , Blum, S. , Dushaj, K. , Madigan, M. , Braverman, E. , Oscar-Bermanm, M. , (2014) Hypothesizing “Reward” Gene Polymorphisms May Predict High Rates of Injury and Addiction in the Workforce: A Nutrient and Electrotherapeutic Based Solution. Health, 6, 2261-2285. doi: 10.4236/health.2014.616262.
References
[1]   Office of Applied Studies (2009) Substance Abuse and Mental Health Statistics from SAMHSA’s Office of Applied Studies (OAS).
http://www.oas.samhsa.gov/data.cfm

[2]   Substance Abuse and Mental Health Services Administration Center for Substance Abuse Prevention (2008) Substance Abuse Prevention Dollars and Cents: A Cost Benefit Analysis. US Department of Health and Human Services. (SMA) 07-4298, Washington DC.

[3]   Office of National Drug Control Policy (2012) What America’s Users Spend on Illegal Drugs, 2000-2006. Executive Office of the President, Washington DC.

[4]   Substance Abuse and Mental Health Services Administration (2004) Overview of Findings from the 2003 National Survey on Drug Use and Health (Office of Applied Studies, NSDUH Series H-24, DHHS Publication No. SMA 04-3963). Rockville.

[5]   Wickizer, T.M. (2013) State-Level Estimates of the Economic Costs of Alcohol and Drug Abuse. Journal of Health Care Finance, 39, 71-84.

[6]   Matano, R.A., Wanat, S.F., Westrup, D., Koopman, C. and Whitsell, S.D. (2002) Prevalence of Alcohol and Drug Use in a Highly Educated Workforce. Journal of Behavioral Health Services & Research, 29, 30-44.
http://dx.doi.org/10.1007/BF02287830

[7]   Boden, L.I. (2006) Occupational Injury and Illness Meet the Labor Market. Annals of the New York Academy of Sciences, 1076, 858-870.
http://dx.doi.org/10.1196/annals.1371.011

[8]   Wetmorland, M.G. and Buys, N. (2004) A Comparison of Disability Management Practices in Australian and Canadian Workplaces. Work, 23, 31-41.

[9]   Melhorn, J.M. (2001) Occupational Orthopaedics in This Millennium. Clinical Orthopaedics & Related Research, 385, 23-35.

[10]   Khan, J., Gerdtham, U.G. and Jansson, B. (2004) Effects of Macroeconomic Trends on Social Security Spending Due to Sickness and Disability. American Journal of Public Health, 94, 2004-2009.
http://dx.doi.org/10.2105/AJPH.94.11.2004

[11]   Yassi, A., Gilbert, M. and Cvitkovich, Y. (2005) Trends in Injuries, Illnesses, and Policies in Canadian Healthcare Workplaces. Canadian Journal of Public Health, 96, 333-339.

[12]   Blum, K. with Payne, J. (1991) Alcohol and the Addictive Brain. The Free Press (Simon and Schuster), New York.

[13]   Blum, K., Braverman, E.R., Wood, R.C., Gill, J., Li, C., Chen, T.J.H., Taub, M., Montgomery, A.R., Cull, J.G. and Sheridan, P.J. (1996) Increased Prevalence of the Taq1 A1 Allele of the Dopamine Receptor Gene in Obesity with Comorbid Substance Use Disorder. Pharmacogenetics, 6, 297-305.

[14]   Blum, K., Braverman, E.R., Holder, J.M., Lubar, J.F., Monastra, V.J., Miller, D., et al. (2000) The Reward Deficiency Syndrome: A Biogenetic Model for the Diagnosis and Treatment of Impulsive, Addictive and Compulsive Behaviors. Journal of Psychoactive Drugs, 32, 1-112. (Supplement)
http://dx.doi.org/10.1080/02791072.2000.10736099

[15]   Di Chiara, G. (1999) Drug Addiction as Dopamine-Dependent Associative Learning Disorder. European Journal of Pharmacology, 375, 13-30.
http://dx.doi.org/10.1016/S0014-2999(99)00372-6

[16]   Di Chiara, G. (2002) Nucleus Accumbens Shell and Core Dopamine: Differential Role in Behavior and Addiction. Behavioural Brain Research, 137, 75-114.

[17]   Di Chiara, G., Tanda, G., Bassare, V., Pontieri, F., Acquas, E., Fenu, S., Cadoni, C. and Carboni, E. (1999) Drug Addiction as a Disorder of Associative Learning, Role of Nucleus Accumbens Shell/Extended Amygdala Dopamine. Annals of the New York Academy of Sciences, 877, 461-485.
http://dx.doi.org/10.1111/j.1749-6632.1999.tb09283.x

[18]   Koob, G.F. (2000) Neurobiology of Addiction: Toward the Development of New Therapies. Annals of the New York Academy of Sciences, 909, 170-185.
http://dx.doi.org/10.1111/j.1749-6632.2000.tb06682.x

[19]   Koob, G.F. (2003) Alcoholism: Allostasis and Beyond. Alcoholism: Clinical and Experimental Research, 27, 232-243. http://dx.doi.org/10.1097/01.ALC.0000057122.36127.C2

[20]   Koob, G.F. and Le Moal, M. (2001) Drug Addiction, Dysregulation of Reward, and Allostasis. Neuropsychopharmacology, 24, 97-129.
http://dx.doi.org/10.1016/S0893-133X(00)00195-0

[21]   Noble, E.P., Blum, K., Ritchie, T., Montgomery, A. and Sheridan, P. (1991) Allelic Association of the D2 Dopamine Receptor Gene with Receptor-Binding Characteristics. JAMA Psychiatry, 48, 648-654.
http://dx.doi.org/10.1001/archpsyc.1991.01810310066012

[22]   Volkow, N.D., Chang, L., Wang, G.J., Fowler, J.S., Ding, Y.S., Sedler, M., Logan, J., Franceschi, D., Gatley, J., Hitzemann, R., Gifford, A., Wong, C. and Pappas, N. (2001) Low Level of Brain Dopamine D2 Receptors in Methamphetamine Abusers: Association with Metabolism in the Orbitofrontal Cortex. American Journal of Psychiatry, 158, 377-382.
http://dx.doi.org/10.1176/appi.ajp.158.3.377

[23]   Wightman, R.M. and Robinson, D.L. (2002) Transient Changes in Mesolimbic Dopamine and Their Association with “Reward”. Journal of Neurochemistry, 82, 721-735.
http://dx.doi.org/10.1046/j.1471-4159.2002.01005.x

[24]   Blum, K. and Kozlowski, G.P. (1990) Ethanol and Neuromodulator Interactions: A Cascade Model of Reward. In: Ollat, H., Parvez, S. and Parvez, H., Eds., Alcohol and Behavior, VSP Press, Utrecht, 131-149.

[25]   Gessa, G.L., Mutoni, F., Coller, M., Vargin, L. and Mercer, G. (1985) Low Doses of Ethanol Activate Dopaminergic Neurons in the Ventral Tegmental Area. Brain Research, 348, 201-203.
http://dx.doi.org/10.1016/0006-8993(85)90381-6

[26]   Yadid, G., Pacak, K., Kopin, I.J. and Goldstein, D.S. (1994) Endogenous Serotonin Stimulates Striatal Dopamine Release in Conscious Rats. Journal of Pharmacology and Experimental Therapeutics, 270, 1158-1165.

[27]   Parsons, L.H., Weiss, F. and Koob, G.F. (1996) Serotonin 1b Receptor Stimulation Enhances Dopamine-Mediated Reinforcement. Psychopharmacology, 128, 150-160.

[28]   Hallbus, M., Magnusson, T. and Magnusson, O. (1997) Influence of 5-HT1B/1D Receptors on Dopamine Release in the Guinea Pig Nucleus Accumbens: A Microdialysis Study. Neuroscience Letters, 225, 57-60.
http://dx.doi.org/10.1016/S0304-3940(97)00178-X

[29]   Dick, D.M., Bierut, L., Hinrichs, A., Fox, L., Bucholz, K.K., Kramer, J., Kuperman, S., Hesselbrock, V., Schuckit, M., Almasy, L., Tischfield, J., Porjesz, B., Begleiter, H., Nurnberger Jr., J., Xuei, X., Edenberg, H.J. and Foroud, T. (2006) The Role of GABRA2 in Risk for Conduct Disorder and Alcohol and Drug Dependence across Developmental Stages. Behavior Genetics, 36, 577-590.
http://dx.doi.org/10.1007/s10519-005-9041-8

[30]   Adler, C.M., Elman, I., Weisenfield, N., Kestler, L., Pickar, D. and Breier, A. (2000) Effects of Acute Metabolic Stress on Striatal Dopamine Release in Healthy Volunteers. Neuropsychopharmacology, 22, 545-550.
http://dx.doi.org/10.1016/S0893-133X(99)00153-0

[31]   Kelley, A.E. and Berridge, K.C. (2002) The Neuroscience of Natural Rewards: Relevance to Addictive Drugs. Journal of Neuroscience, 22, 3306-3311.

[32]   Robbins, T.W. and Everitt, B.J. (1996) Neurobehavioural Mechanisms of Reward and Motivation. Current Opinion in Neurobiology, 6, 228-236.
http://dx.doi.org/10.1016/S0959-4388(96)80077-8

[33]   Hall, R.D., Bloom, F.E. and Olds, J. (1977) Neuronal and Neurochemical Substrates of Reinforcement. Neurosciences Research Program Bulletin, 15, 131-314.

[34]   Comings, D.E., Comings, B.G., Muhleman, D., Dietz, G., Shahbahrami, B., Tast, D., Knell, E., Kocsis, P., Baumgarten, R., Kovacs, B.W., Levy, D.L., Smith, M., Kane, J.M., Lieberman, A., Klein, D.N., Macmurray, J., Tosk, J., Sverd, J., Gysin, R. and Flanagan, S. (1991) The Dopamine D2 Receptor Locus as a Modifying Gene in Neuropsychiatric Disorders. JAMA, 266, 1793-1800.
http://dx.doi.org/10.1001/jama.1991.03470130073032

[35]   Koob, G.F. (1992) Drug Abuse: Anatomy, Pharmacology and Function of Reward Pathways. Trends in Pharmacological Sciences, 13, 177-184.
http://dx.doi.org/10.1016/0165-6147(92)90060-J

[36]   Nakajima, S. (1989) Subtypes of Dopamine Receptors Involved in the Mechanism of Reinforcement. Neuroscience & Biobehavioral Reviews, 13, 123-128.
http://dx.doi.org/10.1016/S0149-7634(89)80020-X

[37]   Blum, K., Sheridan, P.J., Wood, R.C., Braverman, E.R., Chen, T.J. and Comings, D.E. (1996) The D2 Dopamine Receptor Gene as a Determinant of Reward Deficiency Syndrome. Journal of the Royal Society of Medicine, 89, 396-400.

[38]   Miller, W.B., Pasta, D.J., Macmurray, J., Chiu, C., Wu, H. and Comings, D.E. (1999) Dopamine Receptor Genes Are Associated with Age at First Sexual Intercourse. Journal of Biosocial Science, 31, 43-54.
http://dx.doi.org/10.1017/S0021932099000437

[39]   Comings, D.E., Muhleman, D. and Gysin, R. (1996) Dopamine D2 Receptor (DRD2) Gene and Susceptibility to Posttraumatic Stress Disorder: A Study and Replication. Biological Psychiatry, 40, 368-372.
http://dx.doi.org/10.1016/0006-3223(95)00519-6

[40]   Kreek, M.J. and Koob, G.F. (1998) Drug Dependence: Stress and Dysregulation of Brain Reward Pathways. Drug and Alcohol Dependence, 51, 23-47.
http://dx.doi.org/10.1016/S0376-8716(98)00064-7

[41]   Pani, L., Porcella, A. and Gessa, G.L. (2000) The Role of Stress in the Pathophysiology of the Dopaminergic System. Molecular Psychiatry, 5, 14-21.
http://dx.doi.org/10.1038/sj.mp.4000589

[42]   Robinson, T.E. and Berridge, K.C. (1989) The Neural Basis of Drug Craving an Incentive-Sensitization Theory of Addiction. Brain Research Reviews, 18, 247-291.
http://dx.doi.org/10.1016/0165-0173(93)90013-P

[43]   Gardner, E.L. (1997) Brain Reward Mechanisms. In: Lowenson, J.H., Ruiz, P., Millman, R.B. and Langrod, J.G., Eds., Substance Abuse: A Comprehensive Textbook, 51-58.

[44]   Blum, K., Cull, J.G., Braverman, E.R. and Comings, D.E. (1996) Reward Deficiency Syndrome. The American Scientist, 84, 132-145.

[45]   Comings, D.E. and Blum, K. (2000) Reward Deficiency Syndrome: Genetic Aspects of Behavioral Disorders. Progress in Brain Research, 126, 325-341.
http://dx.doi.org/10.1016/S0079-6123(00)26022-6

[46]   Volkow, N.D., Fowler, J.S. and Wang, G.J. (2002) Role of Dopamine in Drug Reinforcement and Addiction in Humans: Results from Imaging Studies. Behavioural Pharmacology, 13, 355-366.
http://dx.doi.org/10.1097/00008877-200209000-00008

[47]   Di Chiara, G. and Impereto, A. (1988) Drugs Abused by Humans Preferentially Increase Synaptic Dopamine Concentrations in the Mesolimbic Systems of Freely Moving Rats. Proceedings of the National Academy of Sciences of the United States of America, 85, 5274-5278.

[48]   Blum, K., Noble, E.P., Sheridan, P.J., Montgomery, A., Ritchie, T., Jagadeeswaran, P., Nogami, H., Briggs, A.H. and Cohn, J.B. (1990) Allelic Association of Human Dopamine D2 Receptor Gene in Alcoholism. Journal of the American Medical Association, 263, 2055-2060.
http://dx.doi.org/10.1001/jama.1990.03440150063027

[49]   Blum, K., Noble, E.P., Sheridan, P.J., Finley, O., Montgomery, A., Ritchie, T., Ozkaragoz, T., Fitch, R.J., Sadlack, F., Sheffield, D., et al. (1991) Association of the A1 Allele of the D2 Dopamine Receptor Gene with Severe Alcoholism. Alcohol, 8, 409-416.
http://dx.doi.org/10.1016/0741-8329(91)90693-Q

[50]   Blum, K., Noble, E.P., Sheridan, P.J., Montgomery, A., Ritchie, T., Ozkaragoz, T., Fitch, R.J., Wood, R., Finley, O. and Sadlack, F. (1993) Genetic Predisposition in Alcoholism: Association of the D2 Dopamine Receptor TaqI B1 RFLP with Severe Alcoholics. Alcohol, 10, 59-67.
http://dx.doi.org/10.1016/0741-8329(93)90054-R

[51]   Hietata, J., West, C., Syvalahti, E., Nagren, K., Lehikoinen, P., Sonninen, P. and Ruotsalainen, U. (1994) Striatal D2 Dopamine Receptor Binding Characteristics in Vivo in Patients with Alcohol Dependence. Psychopharmacology, 116, 285-290.
http://dx.doi.org/10.1007/BF02245330

[52]   Xu, K., Lichterman, D., Kipsky, R.H., Franke, P., Liu, X., Hu, Y., et al. (2004) Association of Specific Haplotypes of D2 Dopamine Receptor Gene with Vulnerability to Heroin Dependence in Distinct Populations. JAMA Psychiatry, 61, 597-606.
http://dx.doi.org/10.1001/archpsyc.61.6.597

[53]   Volkow, N.D., Wang, G.J., Fowler, J.S., Logan, J., Hitzemann, R., Ding, Y.S., Pappas, N., Shea, C. and Piscani, K. (1996) Decreases in Dopamine Receptors but Not in Dopamine Transporters in Alcoholics. Alcoholism: Clinical and Experimental Research, 20, 1594-1598.
http://dx.doi.org/10.1111/j.1530-0277.1996.tb05936.x

[54]   Myers, R.D. and Robinson, D.E. (1999) Mμ and D2 Receptor Antisense Oligonucleotides Injected in Nucleus Accumbens Suppress High Alcohol Intake in Genetic Drinking HEP Rats. Alcohol, 18, 225-233.
http://dx.doi.org/10.1016/S0741-8329(99)00015-4

[55]   Thanos, P.K., Volkow, N.D., Freimuth, P., Umegaki, H., Ikari, H., Roth, G., Ingram, D.K. and Hitzemann, R. (2001) Overexpression of Dopamine D2 Receptor Gene Reduces Alcohol Self-Administration. Journal of Neurochemistry, 78, 1094-1103.
http://dx.doi.org/10.1046/j.1471-4159.2001.00492.x

[56]   Gilman, S., Koeppe, R.A., Adams, K.M., Junck, L., Kluin, K.J., Johnson-Greene, D., Martorello, S., Heumann, M. and Bandekar, R. (1998) Decreased Striatal Monoaminergic Terminals in Severe Chronic Alcoholism Demonstrated With 11C-Dihydrotetrabenazine and Positron Emission Tomography. Annals of Neurology, 44, 326-333.
http://dx.doi.org/10.1002/ana.410440307

[57]   Comings, D.E., Wu, S., Chiu, C., Ring, R.H, Gade, R., Ahn, C., Macmurray, J.P., Dietz, G. and Muhlman, D. (1996) Polygenic Inheritance of Tourette Syndrome, Stuttering, Attention Deficit Hyperactivity, Conduct, and Oppositional Defiant Disorder: The Additive and Subtractive Effect of the Three Dopaminergic Genes DRD2, DBH, and DAT1. American Journal of Medical Genetics, 67, 264-288.
http://dx.doi.org/10.1002/(SICI)1096-8628(19960531)67:3<264::AID-AJMG4>3.0.CO;2-N

[58]   Comings, D.E., Dietz, G., Johnson, J.P. and MacMurray, J.P. (1999) Association of the Enkephalinase Gene with Low Amplitude P300 Waves. Neuroreport, 10, 2283-2285.
http://dx.doi.org/10.1097/00001756-199908020-00011

[59]   Comings, D.E., Muhlman, D., Ahn, C., Gysin, R. and Flanagan, S.D. (1994) The Dopamine D2 Receptor Gene: A Genetic Risk Factor in Substance Abuse. Drug and Alcohol Dependence, 34, 175-180.
http://dx.doi.org/10.1016/0376-8716(94)90154-6

[60]   Comings, D.E., Gade-Andavolu, R., Gonzalez, N., Wu, S., Muhleman, D., Chen, C., Koh, P., Farwell, K., Blake, H., Dietz, G., Macmurray, J.P., Lesieur, H.R., Rugle, L.J. and Rosenthal, R.J. (2001) The Additive Effect of Neurotransmitter Genes in Pathological Gambling. Clinical Genetics, 60, 107-116.
http://dx.doi.org/10.1034/j.1399-0004.2001.600204.x

[61]   Comings, D., Johnson, P., Dietz, G. and Muhleman, D. (1995) Dopamine D2 Receptor Gene (DRD2) Haplotypes and the Defense Style Questionnaire in Substance Abuse, Tourette Syndrome and Controls. Biological Psychiatry, 37, 798-805.
http://dx.doi.org/10.1016/0006-3223(94)00222-O

[62]   Comings, D.E., Gade-Andavilu, R., Gonzalez, N., Wu, S., Muhlman, D., Blake, H., Chiu, F., Farwell, K., Darakjy, S., Baker, R., Dietz, G., Saucier, G. and Macmurray, J.P. (2000) Multivariate Analysis of Associations of 42 Genes in ADHD, ODD and Conduct Disorder. Clinical Genetics, 58, 31-40.
http://dx.doi.org/10.1034/j.1399-0004.2000.580106.x

[63]   Noble, E.P., Gottschalk, L.A., Fallon, J.H., Ritchie, T.L. and Wu, J.C. (1997) D2 Dopamine Receptor Polymorphism and Brain Regional Glucose Metabolism. American Journal of Medical Genetics, 74, 162-166.
http://dx.doi.org/10.1002/(SICI)1096-8628(19970418)74:2<162::AID-AJMG9>3.0.CO;2-W

[64]   Noble, E.P., Noble, R.E., Ritchie, T., Syndulko, K., Bohlman, M.C., Noble, L.A., Sparkes, R.S. and Grandy, D.K. (1994) D2 Dopamine Receptor Gene and Obesity. International Journal of Eating Disorders, 15, 205-217.
http://dx.doi.org/10.1002/1098-108X(199404)15:3<205::AID-EAT2260150303>3.0.CO;2-P

[65]   Noble, E.P., Ozkaragoz, T.Z., Ritchie, T., Zhang, X., Bekin, T.R. and Sparkes, R.S. (1998) D2 and D4 Dopamine Receptor Poymorphisms and Personality. American Journal of Medical Genetics, 81, 257-267.
http://dx.doi.org/10.1002/(SICI)1096-8628(19980508)81:3<257::AID-AJMG10>3.0.CO;2-E

[66]   Noble, E.P., Syndilko, K., Fitch, R.J., Ritchie, T., Bohlman, M.C., Gith, P., Sherifan, P.J., Montgomery, A., Heinzman, C., Sparkes, R.S. and Blum, K. (1994) D2 Dopamine Receptor Taq1 a Alleles in Medically Ill Alcoholic and Nonalcoholic Patients. Alcohol and Alcoholism, 29, 729-744.

[67]   Noble, E.P., Zhang, X., Ritchie, T., Lawford, B.R., Grosser, S.C., Young, R.M. and Sparkes, R.S. (1998) D2 Dopamine Receptor and GABA (A) Receptor Beta3 Subunit Gene Alcoholism. Psychiatry Research, 81, 133-147.
http://dx.doi.org/10.1016/S0165-1781(98)00084-5

[68]   Noble, E.P. (2003) D2 Dopamine Receptor Gene in Psychiatric and Neurologic Disorders and Its Phenotypes. American Journal of Medical Genetics Part B, 116B, 103-125.
http://dx.doi.org/10.1002/ajmg.b.10005

[69]   Miller, W.B., Pasta, D.J., Macmurray, J., Chiu, C., Wu, H. and Comings, D.E. (1999) Dopamine Receptor Genes Are Associated with Age at First Sexual Intercourse. Journal of Biosocial Science, 31, 43-54.
http://dx.doi.org/10.1017/S0021932099000437

[70]   Bau, C.H.D., Almeida, S. and Hutz, M.H. (2000) The Taqi A1 Allele of the Dopamine D2 Receptor Gene and Alcoholism in Brazil: Association and Interaction with Stress and Harm Avoidance on Severity Prediction. American Journal of Medical Genetics, 96, 302-306.
http://dx.doi.org/10.1002/1096-8628(20000612)96:3<302::AID-AJMG13>3.0.CO;2-I

[71]   Uhl, G., Blum, K., Noble, E. and Smith, S. (1993) Substance Abuse Vulnerability and D2 Receptor Genes. Trends in Neurosciences, 16, 83-88.
http://dx.doi.org/10.1016/0166-2236(93)90128-9

[72]   Volkow, N.D., Wang, J.G., Beglieter, H., Porjesz, B., Fowler, J.S., Telang, F., Wong, C., Ma, Y., Logan, J., Goldstein, R., Alexoff, D. and Thanos, P.K. (2006) High Levels of Dopamine D2 in Unaffected Members of Alcoholic Families. JAMA Psychiatry, 63, 999-1008.
http://dx.doi.org/10.1001/archpsyc.63.9.999

[73]   Lesch, K.P. (2005) Genetic Alterations of the Murine Serotonergic Gene Pathway: The Neurodevelopmental Basis of Anxiety. Handbook of Experimental Pharmacology, 169, 71-112.
http://dx.doi.org/10.1007/3-540-28082-0_3

[74]   Nellissery, M., Feinn, R.S., Covault, J., Gelernter, J., Anton, R.F., Pettinati, H., Moak, D., Mueller, T. and Kranzler, H.R. (2003) Alleles of a Functional Serotonin Transporter Promoter Polymorphism Are Associated with Major Depression in Alcoholics. Alcoholism: Clinical and Experimental Research, 27, 1402-1408.
http://dx.doi.org/10.1097/01.ALC.0000085588.11073.BB

[75]   Crabbe, J.C., Phillips, T.J., Harris, R.A., Arends, M.A. and Koob, G.F. (2006) Alcohol-Related Genes: Contributions from Studies with Genetically Engineered Mice. Addiction Biology, 11, 195-269.
http://dx.doi.org/10.1111/j.1369-1600.2006.00038.x

[76]   Edenberg, H.J. and Kranzler, H.R. (2005) The Contribution of Genetics to Addiction Therapy Approaches. Pharmacology & Therapeutics, 108, 86-93.
http://dx.doi.org/10.1016/j.pharmthera.2005.06.011

[77]   Sinha, R., Cloninger, C.R. and Parsian, A. (2003) Linkage Disequilibrium and Haplotype Analysis between Serotonin Receptor 1B Gene Variations and Subtypes of Alcoholism. American Journal of Medical Genetics Part B: Neuro-psychiatric Genetics, 121, 83-88.
http://dx.doi.org/10.1002/ajmg.b.20064

[78]   Hill, E.M., Stoltenberg, S.F., Bullard, K.H., Li, S., Zucker, R.A. and Burmeister, M. (2002) Antisocial Alcoholism and Serotonin-Related Polymorphisms: Association Tests. Psychiatric Genetics, 12, 143-153.
http://dx.doi.org/10.1097/00041444-200209000-00005

[79]   Sun, H.F., Chang, Y.T., Fann, C.S., Chang, C.J., Chen, Y.H., Hsu, Y.P., Yu, W.Y. and Cheng, A.T. (2002) Association Study of Novel Human Serotonin 5-HT(1B) Polymorphisms with Alcohol Dependence in Taiwanese Han. Biological Psychiatry, 51, 896-901.
http://dx.doi.org/10.1016/S0006-3223(01)01366-X

[80]   Kranzler, H.R., Hernandez-Avila, C.A. and Gelernter, J. (2002) Polymorphism of the 5-HT1B Receptor Gene (HTR1B): Strong Within-Locus Linkage Disequilibrium without Association to Antisocial Substance Dependence. Neuropsychopharmacology, 26, 115-122.
http://dx.doi.org/10.1016/S0893-133X(01)00283-4

[81]   Parsian, A. and Cloninger, C.R. (2001) Serotonergic Pathway Genes and Subtypes of Alcoholism: Association Studies. Psychiatric Genetics, 11, 89-94.
http://dx.doi.org/10.1097/00041444-200106000-00006

[82]   Fehr, C., Schleicher, A., Szegedi, A., Anghelescu, I., Klawe, C., Hiemke, C. and Dahmen, N. (2001) Serotonergic Polymorphisms in Patients Suffering from Alcoholism, Anxiety Disorders and Narcolepsy. Progress in Neuro-Psycho-pharmacology and Biological Psychiatry, 25, 965-982.
http://dx.doi.org/10.1016/S0278-5846(01)00171-3

[83]   Preuss, U.W., Koller, G., Bondy, B., Bahlmann, M. and Soyka, M. (2001) Impulsive Traits and 5-HT2A Receptor Promoter Polymorphism in Alcohol Dependents: Possible Association but No Influence of Personality Disorders. Neuropsychobiology, 43, 186-191.
http://dx.doi.org/10.1159/000054888

[84]   Fehr, C., Szegedi, A., Anghelescu, I., Klawe, C., Hiemke, C. and Dahmen, N. (2000) Sex Differences in Allelic Frequencies of the 5-HT2C Cys23Ser Polymorphism in Psychiatric Patients and Healthy Volunteers: Findings from Anassociation Study. Psychiatric Genetics, 10, 59-65.
http://dx.doi.org/10.1097/00041444-200010020-00001

[85]   Comings, D.E., Gade, R., Muhleman, D., Chiu, C., Wu, S., To, M., Spence, M., Dietz, G., Winn-Deen, E., Rosenthal, R.J., Lesieur, H.R., Rugle, L., Sverd, J., Ferry, L., Johnson, J.P. and Macmurray, J.P. (1996) Exon and Intron Variants in the Human Tryptophan 2,3-Dioxygenase Gene: Potential Association with Tourette Syndrome, Substance Abuse and Other Disorders. Pharmacogenetics, 6, 307-318.
http://dx.doi.org/10.1097/00008571-199608000-00004

[86]   Lam, S., Shen, Y., Nguyen, T., Messier, T.L., Brann, M., Comings, D., George, S.R. and O’Dowd, B.F. (1996) A Serotonin Receptor Gene (5HT1A) Variant Found in a Tourette’s Syndrome Patient. Biochemical and Biophysical Research Communications, 219, 853-858.
http://dx.doi.org/10.1006/bbrc.1996.0322

[87]   Contini, V., Marques, F.Z., Garcia, C.E., Hutz, M.H. and Bau, C.H. (2006) MAOA-uVNTR Polymorphism in a Brazilian Sample: Further Support for the Association with Impulsive Behaviors and Alcohol Dependence. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 141, 305-308.
http://dx.doi.org/10.1002/ajmg.b.30290

[88]   Eriksson, M., Berggren, U., Blennow, K., Fahlke, C., Mansson, J.E. and Balldin, J. (2000) Alcoholics with the Dopamine Receptor DRD2 A1 Allele Have Lower Platelet Monoamine Oxidase-B Activity than Those with the A2 Allele: A Preliminary Study. Alcohol and Alcoholism, 35, 493-498.
http://dx.doi.org/10.1093/alcalc/35.5.493

[89]   Schmidt, L.G., Sander, T., Kuhn, S., Smolka, M., Rommelspacher, H., Samochowiec, J. and Lesch, K.P. (2000) Different Allele Distribution of a Regulatory MAOA Gene Promoter Polymorphism in Antisocial and Anxious-Depressive Alcoholics. Journal of Neural Transmission, 107, 681-689.
http://dx.doi.org/10.1007/s007020070069

[90]   Blum, K., Chen, T.J.H., Meshkin, B., Waite, R.L., Downs, W.B., Blum, S.H., Mengucci, J.F., Arcuri, V., Braverman, E.R. and Paloma, T. (2007) Manipulation of Catechol-O-Methyl Transferase (COMT) Activity to Influence the Attenuation of Substance Seeking Behavior, a Subtype of Reward Deficiency Syndrome (RDS), Is Dependent upon Gene Polymorphisms: A Hypothesis. Medical Hypotheses, 69, 1054-1060.
http://dx.doi.org/10.1016/j.mehy.2006.12.062

[91]   Kim, B.N., Hwang, J.W., Shin, M.S., Hong, K.E. and Cho, S.C. (2005) Positive Association between Tourette’s Disorder and Catechol-O-Methyl Transferase Gene in Korean Subjects. Psychiatry Investigation, 2, 85-91.

[92]   Long, J.C., Knowler, W.C., Hanson, R.L., Robin, R.W., Urbanek, M., Moore, E., Bennett, P.H. and Goldman, D. (1998) Evidence for Genetic Linkage to Alcohol Dependence on Chromosomes 4 and 11 from an Autosome-Wide Scan in an American Indian Population. American Journal of Medical Genetics, 81, 216-221.
http://dx.doi.org/10.1002/(SICI)1096-8628(19980508)81:3<216::AID-AJMG2>3.0.CO;2-U

[93]   Tiihonen, J., Hallikainen, T., Lachman, H., Saito, T., Volavka, J., Kauhanen, J., et al. (1999) Association between the Functional Variant of the Catechol-O-Methlytransferase (COMT) Gene and Type 1 Alcoholism. Molecular Psychiatry, 4, 286-289.
http://dx.doi.org/10.1038/sj.mp.4000509

[94]   Hosak, L., Libiger, J., Cizek, J., Beranek, M. and Cermakova, E. (2006) The COMT Val158Met Polymorphism Is Associated with Novelty Seeking in Czech Methamphetamine Abusers: Preliminary Results. Neuro Endocrinology Letters, 27, 799-802.

[95]   Blum, K., Futterman, S., Wallace, J.E. and Schwertner, H.A. (1977) Naloxone-Induced Inhibition of Ethanol Dependence in Mice. Nature, 265, 49-51.
http://dx.doi.org/10.1038/265049a0

[96]   Blum, K., Briggs, A.H., Elston, S.F., Delallo, L., Sheridan, P.J. and Sar, M. (1982) Reduced Leucine-Enkephalin— Like Immunoreactive Substance in Hamster Basal Ganglia after Long-Term Ethanol Exposure. Science, 216, 1425-1427.

[97]   Hollt, V., Haarmann, I. and Herz, A. (1981) Long-Term Treatment of Rats with Morphine Reduces the Activity of Messenger Ribonucleic Acid Coding for the Beta-Endorphin/ACTH Precursor in the Intermediate Pituitary. Journal of Neurochemistry, 37, 619-626.
http://dx.doi.org/10.1111/j.1471-4159.1982.tb12532.x

[98]   Genazzani, A.R., Nappi, G., Facchinetti, F., Mazzella, G.L., Parrini, D., Sinforiani, E., Petraglia, F. and Savoldi, F. (1982) Central Deficiency of Beta-Endorphin in Alcohol Addicts. Journal of Clinical Endocrinology & Metabolism, 55, 583-586.
http://dx.doi.org/10.1210/jcem-55-3-583

[99]   Blum, K. and Topel, H. (1986) Opioid Peptides and Alcoholism: Genetic Deficiency and Chemical Management. Functional Neurology, 1, 71-83.

[100]   Gianouculakis, C. (2004) Endogenous Opioids and Addiction in Alcohol and Other Drugs of Abuse. Current Topics in Medicinal Chemistry, 4, 39-50.
http://dx.doi.org/10.2174/1568026043451573

[101]   Ratsma, J.E., Van Der Stelt, O. and Gunning, W.B. (2002) Neurochemical Markers of Alcoholism Vulnerability in Humans. Alcohol and Alcoholism, 37, 523-533.
http://dx.doi.org/10.1093/alcalc/37.6.522

[102]   Blum, K., Noble, E.P., Sheridan, P.J., Montgomery, A., Ritchie, T., Ozkaragoz, T., Fitch, R.J., Wood, R., Finley, O. and Sadlack, F. (1993) Genetic Predisposition in Alcoholism: Association of the D2 Dopamine Receptor TaqI B1 RFLP with Severe Alcoholics. Alcohol, 10, 59-67.
http://dx.doi.org/10.1016/0741-8329(93)90054-R

[103]   Krystal, J.H., D’souza, D.C., Gallinat, J., Driesen, N., Abi-Dargham, A., Petrakis, I., Heinz, A. and Pearlson, G. (2006) The Vulnerability to Alcohol and Substance Abuse in Individuals Diagnosed with Schizophrenia. Neurotoxicity Research, 10, 235-252.
http://dx.doi.org/10.1007/BF03033360

[104]   Lappalainen, J., Krupitsky, E., Kranzler, H.R., Luo, X., Remizov, M., Pchelina, S., Taraskina, A., Zvartau, E., Rasanen, P., Makikyro, T., Somberg, L.K., Krystal, J.H., Stein, M.B. and Gelernter, J. (2006) Mutation Screen of the GAD2 Gene and Association Study of Alcoholism in Three Populations. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 144, 183-192.

[105]   Young, R.M., Lawford, B.R., Feeney, G.F., Ritchie, T. and Noble, E.P. (2004) Alcohol-Related Expectancies Are Associated with the D2 Dopamine Receptor and GABAA Receptor Beta3 Subunit Genes. Psychiatry Research, 127, 171-183.
http://dx.doi.org/10.1016/j.psychres.2003.11.004

[106]   Radel, M., Vallejo, R.L., Iwata, N., Aragon, R., Long, J.C., Virkkunen, M. and Goldman, D. (2005) Haplotype-Based Localization of an Alcohol Dependence Gene to the 5q34 γ-Aminobutyric Acid Type A Gene Cluster. JAMA Psychiatry, 62, 47-55.
http://dx.doi.org/10.1001/archpsyc.62.1.47

[107]   Brady, R.O. (1994) Potential Gene Therapy for Alcoholism. EXS, 71, 383-393.

[108]   Blum, K., Wallace, J.E., Trachtenberg, M.C., Delallo, L. and Wallace, J.E. (1987) Enkephalinase Inhibition: Regulation of Ethanol Intake in Genetically Predisposed Mice. Alcohol, 4, 449-456.
http://dx.doi.org/10.1016/0741-8329(87)90084-X

[109]   Carelli, R.M. (2004) Nucleus Accumbens Cell Firing and Rapid Dopamine Signaling during Goal-Directed Behaviors in Rats. Neuropharmacology, 47, 180-189.
http://dx.doi.org/10.1016/j.neuropharm.2004.07.017

[110]   Carboni, E., Silvagni, A., Rolando, M.T. and Di Chiara, G. (2000) Stimulation of in Vivo Dopamine Transmission in the Bed Nucleus of Stria Terminalis by Reinforcing Drugs. Journal of Neuroscience, 20, 102.

[111]   Blum, K., Elston, S.F., Delallo, L., Briggs, A.H. and Wallace, J.E. (1983) Ethanol Acceptance as a Function of Genotype Amounts of Brain (Met) Enkephalin. Proceedings of the National Academy of Sciences of the United States of America, 80, 6510-6520.

[112]   Sinclair, J.D., Le, A.D. and Kiianmaa, K. (1989) The AA and ANA Rat Lines, Selected for Differences in Voluntary Alcohol Consumption. Experientia, 45, 798-805.
http://dx.doi.org/10.1007/BF01954055

[113]   Strother, W.N., Lumeng, L., Li, T.K. and Mcbride, W.J. (2005) Dopamine and Serotonin Content in Select Brain Regions of Weanling and Adult Alcohol Drinking Rat Lines. Pharmacology Biochemistry and Behavior, 80, 229-237.
http://dx.doi.org/10.1016/j.pbb.2004.11.003

[114]   Syvaelahti, E.K., Pohjalainen, T., Korpi, E.R., Palvimaki, E.P., Ovaska, T., Kuoppamaki, M. and Hietala, J. (1994) Dopamine D2 Receptor Gene Expression in Rat Lines Selected for Differences in Voluntary Alcohol Consumption. Alcoholism: Clinical and Experimental Research, 18, 1029-1031.
http://dx.doi.org/10.1111/j.1530-0277.1994.tb00078.x

[115]   Mcbride, W.J., Chernet, E., Russell, R.N., Wong, D.T., Guan, X.M., Lumeng, L. and Li, T.K. (1997) Regional CNS Densities of Monoamine Receptors in Alcohol-Naive Alcohol-Preferring P and Nonpreferring NP Rats. Alcohol, 14, 141-148.
http://dx.doi.org/10.1016/S0741-8329(96)00117-6

[116]   Lawford, B.R., Young, R.M., Rowell, J.A., Qualichefski, J., Fletcher, B.H., Syndulko, K., Ritchie, T. and Noble, E.P. (1995) Bromocriptine in the Treatment of Alcoholics with the D2 Dopamine Receptor A1 Allele. Nature Medicine, 1, 337-341.
http://dx.doi.org/10.1038/nm0495-337

[117]   Blum, K., Chen, T.J.H., Downs, W.B., Meshkin, B., Blum, S.H., Martinez –Pons, M., Mengucci, J.F., Waite, R.L., Acruri, V., Varshofsiky, M. and Braverman, E.R. (2007) KB220Z (Sg8839),TM an Amino-Acid Enkephalinase Inhibition Nutraceutical Improves Recovery of Alcoholics, a Subtype of Reward Deficiency Syndrome (RDS). Trends in Applied Sciences Research, 2, 132-138.

[118]   Grant, K.E., Chandler, R.M., Castle, A.L. and Ivy, J.L. (1997) Chromium and Exercise Training: Effect on Obese Women. J Am Coll Sports Med, 29, 992-998.

[119]   Blum, K., Trachtenberg, M.C., Elliott, C.E., Dingler, M.L., Sexton, R.L., Samuels, A.I. and Cataldie, L. (1989) Enkephalinase Inhibition and Precursor Amino Acid Loading Improves Inpatient Treatment of Alcoholics and Poly-Drug Abusers: A Double Blind Placebo Controlled Study of the Neuronutrient Intervention Adjunct SAAVE. Alcohol, 5, 481-493.
http://dx.doi.org/10.1016/0741-8329(88)90087-0

[120]   Brown, R.P., Blum, K. and Trachtenberg, M.C. (1990) Neurodynamics of Relapse Prevention: A Neuronutrient Approach to Outpatient DUI Offenders. Journal of Psychoactive Drugs, 22, 173-187.
http://dx.doi.org/10.1080/02791072.1990.10472542

[121]   Blum, K., Trachtenberg, M.C. and Ramsey, J. (1988) Improvement of Inpatient Treatment of the Alcoholic as a Function of Neuronutrient Restoration: A Pilot Study. International Journal of Addiction, 123, 991-998.

[122]   Blum, K. and Tractenberg, M.C. (1988) Neurogenic Deficits Caused by Alcoholism: Restoration by SAAVE, a Neuronutrient Intervention Adjunct. Journal of Psychoactive Drugs, 20, 297-313.
http://dx.doi.org/10.1080/02791072.1988.10472500

[123]   Blum, K., Allison, D., Trachtenberg, M.C., Williams, R.W. and Loeblich, L.A. (1988) Reduction of both Drug Hunger and Withdrawal against Advice Rate of Cocaine Abusers in a 30 Day Inpatient Treatment Program by the Neuronutrient Tropamine. Current Therapeutic Research, 43, 1204.

[124]   Blum, K., et al. (1990) Neuronutrient Effects on Weight Loss on Carbohydrate Bingeing in an Outpatient Bariatrics Setting. Current Therapeutic Research, 48, 217.

[125]   Blum, K., Cull, J.G., Chen, J.H.T., Garcia-Swan, S., Holder, J.M., Wood, R., Braverman, E.R., Bucci, L.R. and Trachtenberg, M.G. (1997) Clinical Evidence for Effectiveness of PhencalTM in Maintaining Weight Loss in an Open-Label, Controlled, 2-Year Study. Current Therapeutic Research, 58, 745-763.
http://dx.doi.org/10.1016/S0011-393X(97)80108-7

[126]   Kaats, G.R., Wise, J.A., Blum, K., Morin, R.J., et al. (1992) The Short-Term Therapeutic Efficacy of Treating Obesity with a Plan of Improved Nutrition and Moderate Caloric Restriction. Current Therapeutic Research, 51, 261-274.

[127]   Kaats, G.R., Blum, K., Pullin, D., Keith, S.C. and Wood, R. (1998) A Randomized, Double-Masked, Placebo-Controlled Study of the Effects of Chromium Picolinate Supplementation on Body Composition: A Replication and Extension of a Previous Study. Current Therapeutic Research, 59, 379-388.
http://dx.doi.org/10.1016/S0011-393X(98)85040-6

[128]   Kaats, G.R., Blum, K., Fisher, J.A. and Adelman, J.A. (1996) Effects of Chromium Picolinate Supplementation on Body Composition: A Randomized, Double Masked, Placebo-Controlled Study. Current Therapeutic Research, 57, 747-756.
http://dx.doi.org/10.1016/S0011-393X(96)80080-4

[129]   Defrance, J.J., Hymel, C., Trachtenberg, M.C., et al. (1997) Enhancement of Attention Processing by Kantrol in Healthy Humans: A Pilot Study. Clinical EEG and Neuroscience, 28, 68-75.
http://dx.doi.org/10.1177/155005949702800204

[130]   Lachman, H.M., Papolos, D.F., Saito, T., Yu, Y.M., Szumlanski, C.L. and Weinshilboum, R.M. (1996) Human Catechol-O-Methytransferase Pharmacogenetics: Description of a Functional Polymorphism and Its Potential Application to Neuropsychiatric Disorders. Pharmacogenetics, 6, 243-250.
http://dx.doi.org/10.1097/00008571-199606000-00007

[131]   Tiihonen, J., Hallikainen, T., Lachman, H., Saito, T., Volavka, J., Kauhanen, J., et al. (1999) Association between the Functional Variant of the Catechol-O-Methlytransferase (COMT) Gene and Type 1 Alcoholism. Molecular Psychiatry, 4, 286-289.
http://dx.doi.org/10.1038/sj.mp.4000509

[132]   Kauhanen, J., Hallikainen, T., Tuomainen, T.P., Koulu, M., Karvonen, M.K., Salonen, J.T. and Tiihonen, J. (2000) Association between the Functional Polymorphism of Catechol-O-Methyltransferase Gene and Alcohol Consumption among Social Drinkers. Alcoholism: Clinical and Experimental Research, 24, 135-139.
http://dx.doi.org/10.1111/j.1530-0277.2000.tb04582.x

[133]   Hunley, K. and Long, J.C. (2005) Gene Flow across Linguistic Boundaries in Native North American Populations. Proceedings of the National Academy of Sciences of the United States of America, 102, 1312-1317.
http://dx.doi.org/10.1073/pnas.0409301102

[134]   Stancheva, S.L. and Mosharrof, A. (1987) Effect of the Extract of Rhodiola rosea L. on the Content of the Brain Biogenic Monoamines. Medecine Physiologie Comptes Rendus De l'Academie Bulgare Des Sciences, 40, 85-87.

[135]   Wurtman, J.J. and Wurtman, R.J. (1979) Drugs that Enhance Serotonergic Transmission Diminish Elective Carbohydrate Consumption by Rats. Life Sciences, 24, 895-903.
http://dx.doi.org/10.1016/0024-3205(79)90339-4

[136]   Young, S.N. (1986) The Clinical Psychopharmacology of Tryptophan. In: Wurtman, R.S. and Wurtman, J.J., Eds., Nutrition and the Brain, Vol. 7, Raven Press, New York, 49-88.

[137]   Ehrenpreis, S. (1982) D-Phenylalanine and Other Enkephalinase Inhibitors as Pharmacological Agents: Implications for Some Important Therapeutic Application. Subs Alcohol Actions Misuse, 3, 231-239.

[138]   Anderson, R.A. (1998) Recent Advances in the Clinical and Biochemical Manifestation of Chromium Deficiency in Human and Animal Nutrition. Journal of Trace Elements in Experimental Medicine, 11, 241-250.
http://dx.doi.org/10.1002/(SICI)1520-670X(1998)11:2/3<241::AID-JTRA14>3.0.CO;2-R

[139]   Cold, J.A. (1996) Neurecover-SA in the Treatment of Cocaine Withdrawal and Craving: A Pilot Study. Clinical Drug Investigation, 12, 1-7.
http://dx.doi.org/10.2165/00044011-199612010-00001

[140]   Chen, T.J., Blum, K., Payte, J.T., Schoolfield, J., Hopper, D., Stanford, M. and Braverman, E.R. (2004) Narcotic Antagonists in Drug Dependence: Pilot Study Showing Enhancement of Compliance with SYN-10, Amino-Acid Precursors and Enkephalinase Inhibition Therapy. Medical Hypotheses, 63, 538-548.
http://dx.doi.org/10.1016/j.mehy.2004.02.051

[141]   Thanos, P.K., Volkow, N.D., Freimuth, P., Umegaki, H., Ikari, H., Roth, G., Ingram, D.K. and Hitzemann, R. (2001) Overexpression of Dopamine D2 Receptor Gene Reduces Alcohol Self-Administration. Journal of Neurochemistry, 78, 1094-1103.
http://dx.doi.org/10.1046/j.1471-4159.2001.00492.x

[142]   Ross, J. (2000) Amino-Acid Precursor and Enkephalinase Inhibition Therapy: Evidence for Effectiveness in Treatment of Reward Deficiency Syndrome (RDS), with Particular Emphasis on Eating Disorders. Mol. Psych., 6, S7.

[143]   Blum, K., Chen, T.J.H., Downs, W.B., Gordon, C.A., Blum, S., Mengucci, J.F., Braverman, E.R., Arcuri, V., Varshavskiy, M., Deutch, R., Pons, M.M. and Meshkin, B. (2006) Reward Deficiency Syndrome in Obesity: A Preliminary Cross Sectional Open Trial with a Genotrim Variant. Advances in Therapy, 26, 1040-1051.

[144]   Savage, S.R. (2002) Assessment for Addiction in Pain-Treatment Settings. Clinical Journal of Pain, 18, S28-S38.
http://dx.doi.org/10.1097/00002508-200207001-00004

[145]   Sees, K.L. and Clark, H.W. (1993) Opioid Use in the Treatment of Chronic Pain: Assessment of Addiction. Journal of Pain and Symptom Management, 8, 257-264.
http://dx.doi.org/10.1016/0885-3924(93)90154-N

[146]   Weissman, D.E. and Haddox, J.D. (1989) Opioid Pseudoaddiction—An Iatrogenic Syndrome. Pain, 36, 363-366.
http://dx.doi.org/10.1016/0304-3959(89)90097-3

[147]   Lusher, J., Elander, J., Bevan, D., Telfer, P. and Burton, B. (2006) Analgesic Addiction and Pseudoaddiction in Painful Chronic Illness. Clinical Journal of Pain, 22, 316-324.
http://dx.doi.org/10.1097/01.ajp.0000176360.94644.41

[148]   Miller, N.S., Swiney, T. and Barkin, R.L. (2006) Effects of Opioid Prescription Medication Dependence and Detoxification on Pain Perceptions and Self-Reports. American Journal of Therapeutics, 13, 436-444.
http://dx.doi.org/10.1097/01.mjt.0000212894.35705.90

[149]   Birnbaum, H.G., White, A.G., Reynolds, J.L., Greenberg, P.E., Zhang, M., Vallow, S., Schein, J.R. and Katz, N.P. (2006) Estimated Costs of Prescription Opioid Analgesic Abuse in the United Staes in 2001. Clinical Journal of Pain, 22, 667-676.
http://dx.doi.org/10.1097/01.ajp.0000210915.80417.cf

[150]   Magnusson, J.E. and Martin, R.V. (2002) Additional Evidence for the Involvement of the Basal Ganglia in Formalin-Induced Nociception: The Role of the Nucleus Accumbens. Brain Research, 942, 128-132.
http://dx.doi.org/10.1016/S0006-8993(02)02489-7

[151]   Taylor, B.K., Joshi, C. and Uppal, H. (2003) Stimulation of Dopamine D2 Receptors in the Nucleus Accimbens Inhibits Inflammatory Pain. Brain Research, 987, 135-143.
http://dx.doi.org/10.1016/S0006-8993(03)03318-3

[152]   Hagelberg, N., Forssell, H., Aalto, S., Rinne, J.O., Scheinin, H., Taiminen, T., et al. (2003) Altered Dopamine D2 Receptor Binding in Atypical Facial Pain. Pain, 106, 43-48.
http://dx.doi.org/10.1016/S0304-3959(03)00275-6

[153]   Blum, K., Chen, T.H.J. and Ross, B.D. (2005) Innate Properties of Electrotherapy Device, a Small Fiber Stimulator Provides the Basis for a Paradigm Shift of Electro-Therapeutic Treatment of Pain with Increased Functional Restoration Associated with Human Neuropathies by Affecting Tissue Circulation. Medical Hypotheses, 64, 1066-1067.
http://dx.doi.org/10.1016/j.mehy.2004.11.033

[154]   Blum, K., Chen, J.H.T. and Ross, B.D. (2005) Innate Properties of Electrotherapy Device, a Small Fiber Stimulator Provides the Basis for a Paradigm Shift of Electro-Therapeutic Treatment of Pain with Increased Functional Restoration Associated with Human Neuropathies. Townsend Letters, 101-104.

[155]   Smith, T.L., Callahan, M.F., Blum, K., Dinubile, N.A., Chen, T.J. and Waite, R.L. (2011) H-Wave® Effects on Blood Flow and Angiogenesis in Longitudinal Studies in Rats. Journal of Surgical Orthopaedic Advances, 20, 255-259.

[156]   Smith, T.L., Blum, K., Callahan, M.F., Dinubile, N.A., Chen, T.J. and Waite, R.L. (2009) Electrotherapy Induces Arteriolar Vasodilation in Rat Striated Muscle via Nitric Oxide-Mediated Mechanisms. Journal of Orthopaedic Research, 27, 1248-1251.
http://dx.doi.org/10.1002/jor.20851

[157]   Tsang, B.K., Tajkaushi, K. and Eichhorn, J.H. (1998) Electrical Stimulation Reduces Symptoms of Thermal Hyper-sensitivity from Injury of Sciatic Partial Ligation in Rats. Anesthesia & Analgesia, 86, S1-S551.
http://dx.doi.org/10.1097/00000539-199802001-00001

[158]   Kumar, D. and Marshall, H.J. (1997) Diabetes Peripheral Neuropathy: Amelioration of Pain with Transcutaneous Electrostimulation. Diabetes Care, 20, 1702-1705.
http://dx.doi.org/10.2337/diacare.20.11.1702

[159]   Kumar, D., Alvaro, M.S., Julka, I.S. and Marshall, H.J. (1998) Diabetic Peripheral Neuropathy: Effectiveness of Electrotherapy and Amitriptyline for Symptomatic Relief. Diabetes Care, 21, 1322-1325.
http://dx.doi.org/10.2337/diacare.21.8.1322

[160]   Julka, I.S., Alvaro, M. and Kumar, D. (1998) Beneficial Effects of Electrical Stimulation on Neuropathic Symptoms in Diabetes Patients. Journal of Foot and Ankle Surgery, 37, 191-194.
http://dx.doi.org/10.1016/S1067-2516(98)80109-9

[161]   Blum, K., Dinubulie, N., Chen, T.J.H., Waite, R.L., Schoolfield, J., Martinez-Pons, M., Callahan, M.F., Smith, T.L., Mengucci, J., Blum, S.H. and Meshkin, B. (2006) H-Wave, a Nonpharmacologic Alternative for the Treatment of Patients with Chronic Soft Tissue Inflammation and Neuropathic Pain: A Preliminary Statistical Outcome Study. Advances in Therapy, 23, 446-455.
http://dx.doi.org/10.1007/BF02850166

[162]   Blum, K., Martinez-Pons, M., Dinubulie, N.A., Chen, T.J.H., Waite, R.L., Schoolfield, J., Blum, S.H., Mengucci, J.F., Downs, W.B. and Meshkin, B. (2006) The H-Wave® Small Muscle Fiber Stimulator, a Nonpharmacologic Alternative for the Treatment of Chronic Soft-Tissue Injury and Neuropathic Pain: An Extended Population Observational Study. Advances in Therapy, 23, 739-749.
http://dx.doi.org/10.1007/BF02850314

[163]   Blum, K., Chen, A.L., Chen, T.J., Prihoda, T.J., Schoolfield, J., Dinubile, N., Waite, R.L., Arcuri, V., Kerner, M., Braverman, E.R., Rhoades, P. and Tung, H. (2008) The H-Wave® Device Is an Effective and Safe Non-Pharmacological Analgesic for Chronic Pain: A Meta-Analysis.. Advances in Therapy, 25, 644-657.
http://dx.doi.org/10.1007/s12325-008-0073-3

[164]   Gold, M.S., Blum, K., Oscar-Berman, M. and Braverman, E.R. (2014) Low Dopamine Function in Attention Deficit/ Hyperactivity Disorder: Should Genotyping Signify Early Diagnosis in Children? Postgraduate Medicine, 126, 153-177.
http://dx.doi.org/10.3810/pgm.2014.01.2735

[165]   Blum, K., Femino, J., Teitlebaum, S., Giordano, J., Oscar-Berman, M. and Gold, M. (2013) Molecular Neurobiology of Addiction Recovery: The 12 Steps Program & Fellowship. Springer Briefs in Neuroscience, Springer, New York, London.
http://dx.doi.org/10.1007/978-1-4614-7230-8

 
 
Top