Attention-deficit-hyperactivity disorder and reward deficiency syndrome

Oscar Berman, Marlene; Blum, Kenneth; Chen, Thomas JH; Braverman, Eric; Waite, Roger; Downs, William; Arcuri, Vanessa; Notaro, Ali; Palomo, Tomas; Comings

doi:10.2147/ndt.s2627

Cited by 248Attention Deficit Hyperactivity DisorderNeurotransmitter Receptor Influence on BehaviorSchizophrenia research and treatment

Attention-deficit-hyperactivity disorder and reward deficiency syndrome

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Oscar Berman, Marlene, Blum, Kenneth, Chen, Thomas JH, Braverman, Eric, Waite, Roger, Downs, William, Arcuri, Vanessa, Notaro, Ali +2 more·2008·Neuropsychiatric Disease and Treatment

DOI 10.2147/ndt.s2627PMC PMC2626918

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Abstract

Molecular genetic studies have identified several genes that may mediate susceptibility to attention deficit hyperactivity disorder (ADHD). A consensus of the literature suggests that when there is a dysfunction in the "brain reward cascade," especially in the dopamine system, causing a low or hypo-dopaminergic trait, the brain may require dopamine for individuals to avoid unpleasant feelings. This high-risk genetic trait leads to multiple drug-seeking behaviors, because the drugs activate release of dopamine, which can diminish abnormal cravings. Moreover, this genetic trait is due in part to a form of a gene (DRD(2) A1 allele) that prevents the expression of the normal laying down of dopamine receptors in brain reward sites. This gene, and others involved in neurophysiological processing of specific neurotransmitters, have been associated with deficient functions and predispose individuals to have a high risk for addictive, impulsive, and compulsive behavioral propensities. It has been proposed that genetic variants of dopaminergic genes and other "reward genes" are important common determinants of reward deficiency syndrome (RDS), which we hypothesize includes ADHD as a behavioral subtype. We further hypothesize that early diagnosis through genetic polymorphic identification in combination with DNA-based customized nutraceutical administration to young children may attenuate behavioral symptoms associated with ADHD. Moreover, it is concluded that dopamine and serotonin releasers might be useful therapeutic adjuncts for the treatment of other RDS behavioral subtypes, including addictions.

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Altered function in opioid and acetylcholine systems has been implicated in ADHD.
“However, altered function in both systems has been implicated in ADHD (13, 14).”
From The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities (2018) · cites this paper as [13]

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Result
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Result
Multivariate analysis of associations of 42 genes in ADHD, ODD and conduct disorder
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BackgroundMethodInfluential
Densities of dopamine D2 receptors are reduced in CNS regions of alcohol-preferring P rats
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Background
Clinical and Molecular Genetics of ADHD and Tourette Syndrome
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BackgroundResultInfluential
Association of the 480 bp DAT1 allele with methylphenidate response in a sample of Irish children with ADHD
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Background
An Open-Label, Dose-Ranging Study of Atomoxetine in Children with Attention Deficit Hyperactivity Disorder
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Background
Effects of D1 and D2 dopamine receptor agents on ethanol consumption in the high-alcohol-drinking (HAD) line of rats
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Background
A family-genetic study of girls with DSM-III attention deficit disorder
Faraone, S. V., Biederman, J., Keenan, K. E., & Tsuang, M. T. (1991) · American Journal of Psychiatry · doi:10.1176/ajp.148.1.112 · Cited by 142 · cited 1× · see citing works
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Background
A preliminary mapping of electrical reinforcing effects in the rat brain.
Olds, J. (1956) · Journal of Comparative and Physiological Psychology · doi:10.1037/h0041287 · Cited by 140 · cited 3× · see citing works
“The reward system in the brain was discovered by accident in the 1950s by James Olds (Olds 1956).”
Background
Effects of locally applied D-1 and D-2 receptor agonists and antagonists studied with brain dialysis
Impérato, A., & Chiara, G. D. (1988) · European Journal of Pharmacology · doi:10.1016/0014-2999(88)90284-1 · Cited by 136 · see citing works
Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD
Kent, L., Green, E., Hawi, Z., Kirley, A., Dudbridge, F., Lowe, N., Raybould, R., Langley, K., Bray, N., Fitzgerald, M., et al. (2005) · Molecular Psychiatry · doi:10.1038/sj.mp.4001696 · Cited by 125 · cited 1× · see citing works
“Kent et al (2005) found evidence to support the hypothesis that the gene BDNF (brain-derived neurotrophic factor) located at 11p13 and encoding for a precursor peptide (proBDNF), is associated with ADHD.”
Background
A CONTROLLED STUDY OF SIBLINGS OF HYPERACTIVE CHILDREN
Welner, Z., Welner, A., Stewart, M., Palkes, H. S., & Wish, E. D. (1977) · The Journal of Nervous and Mental Disease · doi:10.1097/00005053-197708000-00004 · Cited by 113 · cited 1× · see citing works
“These siblings also were 5 times more likely to have major depression than control children (Welner et al 1977; August and Stewart 1983).”
Background
Immunostained serotonergic fibers are decreased in selected brain regions of alcohol-preferring rats
Zhou, F. C., Bledsoe, S. B., Lumeng, L., & Li, T. (1991) · Alcohol · doi:10.1016/s0741-8329(91)90034-t · Cited by 110 · cited 1× · see citing works
“Thus, Li and colleagues (Russell et al 1988; Zhou et al 1991; McBride et al 1993, 1994; Li et al 2006) developed strains of alcohol-preferring (P) and non-preferring (NP) rat lines.”
Background
Prolonged P300 latency in children with the D2 dopamine receptor A1 allele.
Noble, E. P., Berman, S. M., Ozkaragoz, T. Z., & Ritchie, T. (1994) · PubMed Central · Cited by 104 · see citing works
Prediction of Heterogeneity in Intelligence and Adult Prognosis by Genetic Polymorphisms in the Dopamine System Among Children With Attention-Deficit/Hyperactivity Disorder
Mill, J. S., Caspi, A., Williams, B. S., Craig, I., Taylor, A., Polo-Tomás, M., Berridge, C. W., Poulton, R., & Moffitt, T. E. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.4.462 · Cited by 102 · cited 1× · see citing works
“Of further interest, Mill et al (2006) presented evidence that polymorphisms in the DRD 4 and DAT 1 genes were associated with variation (compromise) in intellectual functioning among children diagnosed as having ADHD.”
Background
Effect of comorbid symptoms of oppositional defiant disorder on responses to atomoxetine in children with ADHD: a meta-analysis of controlled clinical trial data
Biederman, J., Spencer, T. J., Newcorn, J. H., Gao, H., Milton, D. R., Feldman, P. D., & Witte, M. M. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0565-2 · Cited by 101 · cited 4× · see citing works
“…crossover study compared the effi cacy and safety of LDX (30, 50, or 70 mg) with placebo, with mixed amphetamine salts (extended-release 10, 20, or 30 mg) included as a reference arm of the study, in 52 ADHD children aged 6–12 years in an analog classroom setting (Biederman et al 2007a).”
BackgroundMethodInfluential
Effects of chronic oral methylphenidate on cocaine self-administration and striatal dopamine D2 receptors in rodents
Thanos, P. K., Michaelides, M., Benveniste, H., Wang, G. J., & Volkow, N. D. (2007) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2007.05.020 · Cited by 100 · cited 1× · see citing works
“This concern was recently addressed by Thanos and colleagues (Thanos et al 2007).”
Background
Atomoxetine and Adult Attention-Deficit/Hyperactivity Disorder: The Effects of Comorbidity
Spencer, T. J., Faraone, S. V., Michelson, D., Adler, L. A., Reimherr, F. W., Glatt, S. J., & Biederman, J. (2006) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v67n0312 · Cited by 94 · cited 1× · see citing works
“In addition to the use of stimulant medications, a second class of medications that works primarily on norepinephrine Neuropsychiatric Disease and Treatment 2008:4(5)908 pathways (eg, clonidine, guanifacine, and atomoxetine, can also be quite effective (Perwien et al 2006; Spencer et al 2001, 2006).”
Background
Dopamine-related genes and their relationships to monoamine metabolites in CSF
Jönsson, E. G., Sedvall, G., Brené, S., Gustavsson, P. J., Geijer, T., Terenius, L. Y., Crocq, M., Lannfelt, L., Tylec, A., Sokoloff, P., et al. (1996) · Biological Psychiatry · doi:10.1016/0006-3223(95)00581-1 · Cited by 93 · cited 2× · see citing works
“There was a remarkable similarity to the profi le for the inattention score in the Tourette syndrome subjects, with 12 heterozygotes showing the highest inattention score, and the Jönsson et al (1996) subjects who were 12 heterozygotes had the lowest levels of CSF homovanillic acid.”
MethodResult
Methylphenidate in Hyperactive Boys with Comorbid Tic Disorder: II. Short-Term Behavioral Effects in School Settings
Gadow, K. D., Nolan, E. E., & Sverd, J. (1992) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-199205000-00012 · Cited by 90 · cited 1× · see citing works
“However, consistent with the above mechanism of action of stimulants, signifi cant exacerbation is unusual, and often the tics are unchanged or improve following stimulant treatment (Gadow et al 1992).”
Background
Familial Subtypes of Childhood Hyperactivity
August, G. J., & Stewart, M. A. (1983) · The Journal of Nervous and Mental Disease · doi:10.1097/00005053-198306000-00006 · Cited by 84 · see citing works
Influence of striatal dopamine transporter availability on the response to methylphenidate in adult patients with ADHD
Krause, J., la Fougere, C., Krause, K.-H., Ackenheil, M., & Dresel, S. H. (2005) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-005-0602-x · Cited by 84 · cited 1× · see citing works
“Additionally, Krause et al (2005) investigated whether availability of striatal DAT may have an infl uence on the response of adult ADHD patients to methylphenidate, as measured with SPECT scans.”
Background
A familial factor in minimal brain dysfunction
Safer, D. J. (1973) · Behavior Genetics · doi:10.1007/bf01067657 · Cited by 83 · cited 1× · see citing works
“In actuality, half-siblings who have only half the genetic similarity show a signifi cantly decreased frequency of ADHD (Safer 1973).”
Background
Test of Variables of Attention
Dumont, R., & Willis, J. O. (2008) · Encyclopedia of Special Education · doi:10.1002/9780470373699.speced2078 · Cited by 78 · see citing works
DNA damage in rats after treatment with methylphenidate
Andreazza, A. C., Frey, B. N., Valvassori, S. S., Zanotto, C., Gomes, K. M., Comim, C. M., Cassini, C., Stertz, L., Ribeiro, L. C., Quevedo, J., et al. (2007) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2007.05.012 · Cited by 76 · cited 1× · see citing works
“These results suggest that methylphenidate may induce central and peripheral early DNA damage, but this early damage may be repaired (Andreazza et al 2007).”
Background
Atomoxetine Treatment in Children and Adolescents with Attention-Deficit Hyperactivity Disorder: What Are the Long-Term Health-Related Quality-of-Life Outcomes?
Perwien, A. R., Kratochvil, C. J., Faries, D. E., Vaughan, B. S., Spencer, T., & Brown, R. T. (2006) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2006.16.713 · Cited by 74 · cited 1× · see citing works
“In addition to the use of stimulant medications, a second class of medications that works primarily on norepinephrine Neuropsychiatric Disease and Treatment 2008:4(5)908 pathways (eg, clonidine, guanifacine, and atomoxetine, can also be quite effective (Perwien et al 2006; Spencer et al 2001, 2006).”
Background
Molecular genetic aspects of attention-deficit/hyperactivity disorder
Heiser, P., Friedel, S., Dempfle, A., Konrad, K., SMIDT, J., Grabarkiewicz, J., Herpertz‐Dahlmann, B., Remschmidt, H., & Hebebrand, J. (2004) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2004.09.010 · Cited by 74 · cited 1× · see citing works
“The same authors further showed from longitudinal evidence that these polymorphisms predicted which children with ADHD were at greatest risk for poor adult prognosis (also see Heiser et al 2004; Madras et al 2005; Larsson et al 2006).”
Background
Enkephalinase inhibition and precursor amino acid loading improves inpatient treatment of alcohol and polydrug abusers: Double-blind placebo-controlled study of the nutritional adjunct SAAVE™
Blum, K., Trachtenberg, M. C., Elliott, C. E., Dingler, M. L., Sexton, R. L., Samuels, A. I., & Cataldie, L. (1988) · Alcohol · doi:10.1016/0741-8329(88)90087-0 · Cited by 74 · cited 1× · see citing works
“Nutraceuticals have the advantage that double-blind studies (Blum et al 1988) can be easily carried out.”
BackgroundSelf-citation
Dual dopamine/serotonin releasers as potential medications for stimulante and alcohol addictions
Rothman, R. B., Blough, B. E., & Baumann, M. H. (2007) · The AAPS Journal · doi:10.1208/aapsj0901001 · Cited by 68 · cited 2× · see citing works
“In other recent articles the authors have discussed the potential development of dual dopamine/serotonin releasers for the treatment of substance use disorders (Rothman et al 2007).”
Background
D2 and D4 dopamine receptor gene polymorphisms and personality traits in a young Korean population
Lee, H., Lee, H. S., Kim, Y., Kim, L., Lee, M. S., Jung, I., Suh, K., & Kim, S. (2003) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.20054 · Cited by 65 · cited 2× · see citing works
“Recent associations of certain alleles of both the dopamine D 4 and dopamine D 2 genes and novelty seeking behavior have confi rmed previous work suggesting polygenic inheritance (Comings et al 1996; Lee et al 2003).”
Background
Narcotic antagonists in drug dependence: pilot study showing enhancement of compliance with SYN-10, amino-acid precursors and enkephalinase inhibition therapy
Chen, T. J. H., Blum, K., Payte, J. T., Schoolfield, J. D., Hopper, D., Stanford, M., & Braverman, E. R. (2004) · Medical Hypotheses · doi:10.1016/j.mehy.2004.02.051 · Cited by 59 · cited 4× · see citing works
“It is not unlikely that some combinations of the above compounds, carefully tested in double-blind studies, may play a supporting role in controlling some of the symptoms of ADHD (Blum and Trachtenberg 1988; Blum et al 2000, 2006b; Blum and Payne 1991; Chen et al 2004).”
BackgroundMethodInfluentialSelf-citation
Value of 99mTc-TRODAT-1 SPECT to predict clinical response to methylphenidate treatment in adults with attention deficit hyperactivity disorder
la Fougère, C., Krause, J., Krause, K.-H., Josef Gildehaus, F., Hacker, M., Koch, W., Hahn, K., Tatsch, K., & Dresel, S. (2006) · Nuclear Medicine Communications · doi:10.1097/01.mnm.0000230077.48480.68 · Cited by 57 · cited 1× · see citing works
“(7) Further evidence demonstrated the effectiveness of dopaminergic agonists in the treatment of ADHD (la Fougere et al 2006).”
Background
Report from the 4th International Meeting of the Attention Deficit Hyperactivity Disorder Molecular Genetics Network
Faraone, S. V. (2003) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.20047 · Cited by 57 · cited 2× · see citing works
“…in the dopamine receptor gene, but who have engaged in risky behaviors (such as cocaine abuse, extremely low caloric diet, high levels of stress over an extended period of time), the brain functions as though it had the DRD 2 genetic variant (or other specifi c gene variants) (Faraone 2003).”
Background
Regional serotonin1A receptors in the CNS of alcohol-preferring and -nonpreferring rats
McBride, W. J., Guan, X.-M., Chernet, E., Lumeng, L., & Li, T. (1994) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(94)90449-9 · Cited by 56 · cited 2× · see citing works
“Additional support for this idea came when investigators found that by administering substances that increase the serotonin supply at the synapse, or by stimulating dopamine D 2 receptors directly, they could reduce craving for alcohol (McBride et al 1994).”
Background
The striatum in a putative cerebral network activated by verbal awareness in normals and in ADHD children
Lou, H. C., Andresen, J., Steinberg, B., McLaughlin, T., & Friberg, L. (1998) · European Journal of Neurology · doi:10.1046/j.1468-1331.1998.510067.x · Cited by 47 · cited 1× · see citing works
“However, brain-imaging studies have shown that children with this disorder have an underlying neurological dysfunction, which likely accounts for their behavior (Zametkin et al 1990; Lou et al 1998).”
Background
Unravelling the complexity of attention-deficit hyperactivity disorder: A behavioural genomic approach
Asherson, P. J., Kuntsi, J., & Taylor, E. (2005) · The British Journal of Psychiatry · doi:10.1192/bjp.187.2.103 · Cited by 45 · cited 1× · see citing works
“Chromosomal regions highlighted by replication across studies are Neuropsychiatric Disease and Treatment 2008:4(5)906 accumulating evidence with increasing sample size and include chromosomes 5p13, 6q12, 16p13, and 17p11 (ArcosBurgos et al 2004; Asherson et al 2005).”
Background
Probes for Narcotic Receptor Mediated Phenomena. 34. Synthesis and Structure−Activity Relationships of a Potent μ-Agonist δ-Antagonist and an Exceedingly Potent Antinociceptive in the Enantiomeric C9-Substituted 5-(3-Hydroxyphenyl)-N-phenylethylmorphan Series
Hiebel, A., Lee, Y. S., Bilsky, E. J., Giuvelis, D., Deschamps, J. R., Parrish, D. A., Aceto, M. D. G., May, E. L., Harris, L. S., Coop, A., et al. (2007) · Journal of Medicinal Chemistry · doi:10.1021/jm061325e · Cited by 45 · cited 1× · see citing works
“Finally, they discuss their recently published data about PAL-287 (naphthylisopropylamine), a novel non-amphetamine dopamine/serotonin-releasing agent that suppresses cocaine self-administration but lacks positive reinforcing properties (Hiebel et al 2007).”
Background
Effect of ethanol on [3H]Dopamine release in rat nucleus accumbens and striatal slices
Russell, V. A., Lamm, M. C. L., & Taljaard, J. J. F. (1988) · Neurochemical Research · doi:10.1007/bf01268885 · Cited by 41 · cited 1× · see citing works
“Thus, Li and colleagues (Russell et al 1988; Zhou et al 1991; McBride et al 1993, 1994; Li et al 2006) developed strains of alcohol-preferring (P) and non-preferring (NP) rat lines.”
Background
Association of the calcyon gene (DRD1IP) with attention deficit/hyperactivity disorder
Laurin, N., Misener, V. L., Crosbie, J., Ickowicz, A., Pathare, T., Roberts, W., MALONE, M. A., Tannock, R., Schachar, R. J., Kennedy, J. L., et al. (2005) · Molecular Psychiatry · doi:10.1038/sj.mp.4001737 · Cited by 41 · cited 1× · see citing works
“Other genes that have been associated with ADHD susceptibility include the calcyon gene (DRD11p) (Laurin et al 2005); beta hydroxylase gene (Inkster et al 2004) NR4A2 gene (Smith et al 2005) and the COMT gene (Turic et al 2005b).”
Background
ADHD in adolescence and adulthood, with a special focus on the dopamine transporter and nicotine
Krause, J., Krause, K., Dresel, S. H. J., la Fougère, C. J., & Ackenheil, M. (2006) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2006.8.1/jkrause · Cited by 37 · cited 1× · see citing works
“Dopamine D2 receptors, regional blood fl ow, and response to methylphenidate In reviews of published articles that examined striatal dopamine transporter (DAT) density in ADHD patients, Krause et al (2003; 2006) cited numerous neuroimaging fi ndings of elevation in that region.”
Background
Comparison of Parent and Teacher Reports of Attention-Deficit/Hyperactivity Disorder Symptoms from Two Placebo-Controlled Studies of Atomoxetine in Children
Biederman, J., Gao, H., Rogers, A. K., & Spencer, T. J. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.03.036 · Cited by 34 · cited 1× · see citing works
“People with ADHD also have trouble adapting to change.”
Background
Enhancement of Attention Processing by Kantroll™ in Healthy Humans: A Pilot Study
DeFrance, J. F., Hymel, C., Trachtenberg, M. C., Ginsberg, L. D., Schweitzer, F. C., Estes, S. L., Chen, T. J. H., Braverman, E. R., Cull, J. G., & Blum, K. (1997) · Clinical Electroencephalography · doi:10.1177/155005949702800204 · Cited by 33 · cited 1× · see citing works
“In an early study of healthy volunteers, a combination of amino acids and herbals showed positive results (Defrance et al 1977).”
BackgroundSelf-citation
Genetic Factors in the Hyperkinetic Syndrome
Cantwell, D. P. (1976) · Journal of the American Academy of Child Psychiatry · doi:10.1016/s0002-7138(09)61483-7 · Cited by 33 · see citing works
Neurogenetic interactions and aberrant behavioral co-morbidity of attention deficit hyperactivity disorder (ADHD): dispelling myths
Comings, D. E., Chen, T. J. H., Blum, K., Mengucci, J. F., Blum, S. H., & Meshkin, B. (2005) · Theoretical Biology and Medical Modelling · doi:10.1186/1742-4682-2-50 · Cited by 32 · see citing works
Self-citation
Identification and characterization of human NR4A2 polymorphisms in attention deficit hyperactivity disorder
Smith, K. M., Bauer, L., Fischer, M., Barkley, R. A., & NAVIA, B. A. (2005) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30127 · Cited by 32 · cited 1× · see citing works
“Other genes that have been associated with ADHD susceptibility include the calcyon gene (DRD11p) (Laurin et al 2005); beta hydroxylase gene (Inkster et al 2004) NR4A2 gene (Smith et al 2005) and the COMT gene (Turic et al 2005b).”
Background
A Family Based Study Implicates Solute Carrier Family 1–Member 3 (SLC1A3) Gene in Attention-Deficit/Hyperactivity Disorder
Turic, D., Langley, K., Williams, H. J., Norton, N., Williams, N. M., Moskvina, V., van den Bree, M. B. M., Owen, M. J., Thapar, A., & O’Donovan, M. C. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.03.025 · Cited by 31 · see citing works
Linkage disequilibrium analysis of the dopamine beta-hydroxylase gene in persistent attention deficit hyperactivity disorder
Inkster, B., Muglia, P., Jain, U., & Kennedy, J. (2004) · Psychiatric Genetics · doi:10.1097/01.ypg.0000107932.32051.1c · Cited by 31 · cited 1× · see citing works
“Other genes that have been associated with ADHD susceptibility include the calcyon gene (DRD11p) (Laurin et al 2005); beta hydroxylase gene (Inkster et al 2004) NR4A2 gene (Smith et al 2005) and the COMT gene (Turic et al 2005b).”
Background
A family based study of catechol‐O‐methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD)
Turic, D., Williams, H. J., Langley, K., Owen, M. J., Thapar, A., & O’Donovan, M. C. (2005) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30123 · Cited by 30 · cited 1× · see citing works
“Other genes that have been associated with ADHD susceptibility include the calcyon gene (DRD11p) (Laurin et al 2005); beta hydroxylase gene (Inkster et al 2004) NR4A2 gene (Smith et al 2005) and the COMT gene (Turic et al 2005b).”
Background
Delayed P300 latency correlates with abnormal Test of Variables of Attention (TOVA) in adults and predicts early cognitive decline in a clinical setting
Braverman, E. R., Chen, T. J. H., Schoolfield, J. D., Martinez-Pons, M., Arcuri, V., Varshavskiy, M., Gordon, C. A., Mengucci, J. F., Blum, S. H., Meshkin, B., et al. (2006) · Advances in Therapy · doi:10.1007/bf02850047 · Cited by 28 · see citing works
Self-citation
Fifteen-Year Follow-up of a Behavioral History of Attention Deficit Disorder
Howell, D. C., Huessy, H. R., & Hassuk, B. (1985) · PEDIATRICS · doi:10.1542/peds.76.2.185 · Cited by 28 · see citing works
The Genetics of Attention-Deficit/Hyperactivity Disorder
Pauls, D. L. (2005) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.04.019 · Cited by 24 · see citing works
Alcohol and the Addictive Brain: New Hope for Alcoholics from Biogenetic Research
Blum, K. (1991) · Cited by 17 · see citing works
Self-citation
Neurogenetic Deficits Caused by Alcoholism: Restoration by SAAVE™, a Neuronutrient Intervention Adjunct
Blum, K., & Trachtenberg, M. C. (1988) · Journal of Psychoactive Drugs · doi:10.1080/02791072.1988.10472500 · Cited by 15 · cited 1× · see citing works
“It is not unlikely that some combinations of the above compounds, carefully tested in double-blind studies, may play a supporting role in controlling some of the symptoms of ADHD (Blum and Trachtenberg 1988; Blum et al 2000, 2006b; Blum and Payne 1991; Chen et al 2004).”
BackgroundSelf-citation
DNA based customized nutraceutical “gene therapy” utilizing a genoscore: A hypothesized paradigm shift of a novel approach to the diagnosis, stratification, prognosis and treatment of inflammatory processes in the human
Blum, K., Meshkin, B., & Downs, B. W. (2006) · Medical Hypotheses · doi:10.1016/j.mehy.2005.09.029 · Cited by 15 · cited 2× · see citing works
“It is not unlikely that some combinations of the above compounds, carefully tested in double-blind studies, may play a supporting role in controlling some of the symptoms of ADHD (Blum and Trachtenberg 1988; Blum et al 2000, 2006b; Blum and Payne 1991; Chen et al 2004).”
BackgroundSelf-citation
Second messengers, natural rewards, and drugs of abuse.
Stein, L., & Belluzzi, J. D. (1986) · PubMed · Cited by 14 · see citing works
Overload: Attention Deficit Disorder and the Addictive Brain
Miller, D. K. (1996) · Cited by 14 · see citing works
Overload: Attention Deficit Disorder and the Addictive Brain
Ruel, J. (1997) · Europe PMC (PubMed Central) · Cited by 12 · see citing works
Dual Dopamine/Serotonin Releasers as Potential Medications for Stimulant and Alcohol Addictions
Rothman, R. B., Blough, B. E., & Baumann, M. H. (2008) · Springer eBooks · doi:10.1007/978-0-387-76678-2_19 · Cited by 10 · see citing works
Narcotic antagonists in drug dependence: pilot study showing enhancement of compliance with SYN-10, amino-acid precursors and enkephalinase inhibition therapy
CHEN, T. (2004) · Medical Hypotheses · doi:10.1016/s0306-9877(04)00194-x · Cited by 8 · see citing works
Self-citation
An open-label, dose-ranging study of atomoxetine in children with attention-deficit hyperactivity disorder.
R, M. I. (2002) · Journal of Developmental & Behavioral Pediatrics · doi:10.1097/00004703-200202000-00027 · Cited by 7 · see citing works
Editorial: Pragmatics and statistics in psychiatric genetics
Levinson, D. F. (1997) · American Journal of Medical Genetics · doi:10.1002/(sici)1096-8628(19970418)74:2 · Cited by 6 · see citing works
The relation between childhood antisocial behavior and the dopamine transporter gene (DAT1): Mediation via hyperactivity-impulsivity
Waldman, I. D., Mohr, J., Abramowitz, A. J., Sherman, S. L., Cleveland, H. H., Gard, J. M. C., Giedinghagen, L. N., Stever, C., & Rowe, D. (1998) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · Cited by 2 · see citing works

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Research works printed but not linked: 4

Blum K Meshkin B Downs BW 2006b DNA based customized nutraceutical “gene therapy” utilizing a genoscore: a hypothesized paradigm shift of a novel approach to the diagnosis, stratification, prognosis and treatment of inflammatory processes in the human Med Hypotheses 66 1008 18 16403602
Blum K Sheridan PJ Wood RC 1996b The D2 dopamine receptor gene as a determinant of reward deficiency syndrome J R Soc Med 89 396 400 8774539 PMC1295855
Conners CK 2006 CRS-R (Conners’ Rating Scales-Revised) Minneapolis, MN Pearson Assessment Group
Noble EP Gottschalk LA Fallon JH 1997 D2 dopamine receptor polymorphism and brain regional glucose metabolism Am J Med Genet 74 162 6 9129716

Sorted by citations

EEG delta oscillations as a correlate of basic homeostatic and motivational processes
Knyazev, G. G. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2011.10.002 · Cited by 776 · see citing works
The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities
Faraone, S. V. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.02.001 · Cited by 631 · see citing works
“…has focused on dopamine (DA) and norepinephrine (NE), ADHD has also been linked to dysfunction in serotonin (5hydroxytryptamine [5-HT]), acetylcholine (ACH), opioid, and glutamate (GLU) pathways (Cortese, 2012; Maltezos et al., 2014; Blum et al., 2008; Potter et al., 2014; Elia et al., 2011).”
Ventral–striatal responsiveness during reward anticipation in ADHD and its relation to trait impulsivity in the healthy population: A meta-analytic review of the fMRI literature
Plichta, M. M., & Scheres, A. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.07.012 · Cited by 424 · see citing works
“According to this model, VS-hyporesponsiveness is related to the concept of “reward deficiency syndrome” (Blum et al., 1995, 2008) and motivational toxicity (Bozarth, 1989). The dynamical aspect implicated in this model is best supported by a recent study of Stice et al. (2013). They showed that initial VS-hyperrespon…”
Background
Treatment of internet addiction: a meta-analysis
Winkler, A., Dörsing, B., Rief, W., Shen, Y., & Glombiewski, J. A. (2013) · Clinical Psychology Review · doi:10.1016/j.cpr.2012.12.005 · Cited by 404 · see citing works
New developments in brain research of internet and gaming disorder
Weinstein, A., Livny, A., & Weizman, A. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.01.040 · Cited by 257 · see citing works
&#x201C;Liking&#x201D; and &#x201C;Wanting&#x201D; Linked to Reward Deficiency Syndrome (RDS): Hypothesizing Differential Responsivity in Brain Reward Circuitry
Blum, K., Gardner, E., Oscar-Berman, M., & Gold, M. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212798919110 · Cited by 218 · see citing works
“Credible evidence also implicates serotonergic, opioid, endocannabinoid , GABAergic, and glutamatergic mechanisms in addiction as denoted in the brain reward cascade hypothesis [10].”
BackgroundSelf-citation
Activation instead of blocking mesolimbic dopaminergic reward circuitry is a preferred modality in the long term treatment of reward deficiency syndrome (RDS): a commentary
Blum, K., Chen, A. L., Chen, T. J. H., Braverman, E. R., Reinking, J. L., Blum, S. H., Cassel, K., Downs, B. W., Waite, R. L., Williams, L., et al. (2008) · Theoretical Biology and Medical Modelling · doi:10.1186/1742-4682-5-24 · Cited by 186 · see citing works
Self-citation
The risk of eating disorders comorbid with attention‐deficit/hyperactivity disorder: A systematic review and meta‐analysis
Nazar, B. P., Bernardes, C., Peachey, G., Sergeant, J. A., Mattos, P., & Treasure, J. L. (2016) · International Journal of Eating Disorders · doi:10.1002/eat.22643 · Cited by 180 · see citing works
Understanding the Role of the Gut Microbiome in Brain Development and Its Association With Neurodevelopmental Psychiatric Disorders
Dash, S., Syed, Y. A., & Khan, M. R. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.880544 · Cited by 179 · see citing works
New developments on the neurobiological and pharmaco-genetic mechanisms underlying internet and videogame addiction
Weinstein, A. M., & Lejoyeux, M. (2013) · American Journal on Addictions · doi:10.1111/ajad.12110 · Cited by 168 · see citing works
Automated detection of ADHD: Current trends and future perspective
Loh, H. W., Ooi, C. P., Barua, P. D., Palmer, E. E., Molinari, F., & Acharya, U. R. (2022) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2022.105525 · Cited by 164 · see citing works
Attentional Control and other Executive Functions
Drigas, A. S., & Karyotaki, M. (2017) · International Journal of Emerging Technologies in Learning (iJET) · doi:10.3991/ijet.v12i03.6587 · Cited by 171 · see citing works
Adolescence as a critical window for developing an alcohol use disorder: current findings in neuroscience
Nixon, K., & McClain, J. A. (2010) · Current Opinion in Psychiatry · doi:10.1097/yco.0b013e32833864fe · Cited by 126 · see citing works
Eating Disorders Impact on Vigilance and Decision Making of a Community Sample of Treatment Naive Attention-Deficit/Hyperactivity Disorder Young Adults
Nazar, B. P., Trindade, A. P., Leslie, M. R., Malloy‐Diniz, L. F., Sergeant, J. A., Treasure, J. L., & Mattos, P. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00531 · Cited by 121 · see citing works
“, sleep apnea) in obese patients mimicking ADHD (40), a genetic variant with impaired reward processing or altered eating habits due to impulsivity (41).”
Background
An Update Overview on Brain Imaging Studies of Internet Gaming Disorder
Weinstein, A. M. (2017) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2017.00185 · Cited by 115 · see citing works
“The evidence for genetic dopaminergic vulnerability is compatible with the behavioral addiction model of IGD and consequently, IGD may be classified as a reward deficiency syndrome (101, 102).”
Emerging Association Between Addictive Gaming and Attention-Deficit/Hyperactivity Disorder
Weinstein, A. M., & Weizman, A. (2012) · Current Psychiatry Reports · doi:10.1007/s11920-012-0311-x · Cited by 105 · see citing works
Using chaotic artificial neural networks to model memory in the brain
Aram, Z., Jafari, S., Ma, J., Sprott, J. C., Zendehrouh, S., & Pham, V. (2016) · Communications in Nonlinear Science and Numerical Simulation · doi:10.1016/j.cnsns.2016.08.025 · Cited by 104 · see citing works
“Every type of reward that has been studied and also some stressful situations increase the level of dopamine transmission in the brain [50] .”
Background
Association of Attention-Deficit/Hyperactivity Disorder in Childhood and Adolescence With the Risk of Subsequent Psychotic Disorder
Nourredine, M., Gering, A., Fourneret, P., Rolland, B., Falissard, B., Cucherat, M., Geoffray, M., & Jurek, L. (2021) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2020.4799 · Cited by 103 · see citing works
Dopaminergic dysregulation in mice selectively bred for excessive exercise or obesity
Mathes, W. F., Nehrenberg, D. L., Gordon, R. R., Hua, K., Garland, T., & Pomp, D. (2010) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.02.016 · Cited by 98 · see citing works
“Moreover, disruption of normative neurotransmission within dopaminergic pathways has been implicated in binge eating, obesity, and hyperactivity (Arnsten, 2006; Blum et al., 2008; Davis et al., 2008a; Davis et al., 2009; Geiger et al., 2008; Gruber et al., 2009; Xu et al., 2009).”
Background
Review of electroencephalography signals approaches for mental stress assessment
Attar, E. T. (2022) · Neurosciences · doi:10.17712/nsj.2022.4.20220025 · Cited by 98 · see citing works
Epigenetics in Developmental Disorder: ADHD and Endophenotypes
Archer, T., & Oscar‐Berman, M. (2011) · Journal of Genetic Syndromes & Gene Therapy · doi:10.4172/2157-7412.1000104 · Cited by 92 · see citing works
“[74] discussed the viability of ADHD genetic testing at birth with obvious diagnostic benefits probable via: (a) coupling of genotyping with psychometric instruments, (b) that dopaminergic genotyping to determine high risk future substance abuse may affect use in adolescents, and (c) applications of D2 agonists for AD…”
BackgroundSelf-citation
Neural substrates of trait impulsivity, anhedonia, and irritability: Mechanisms of heterotypic comorbidity between externalizing disorders and unipolar depression
Zisner, A. R., & Beauchaine, T. P. (2016) · Development and Psychopathology · doi:10.1017/s0954579416000754 · Cited by 92 · see citing works
“Several contemporary models of ADHD assert that chronic irritability motivates hyperactivity and excessive reinforcement-seeking behavior, hallmarks of the combined and hyperactive–impulsive presentations (Blum et al. 2000, 2008; Sagvolden et al., 2005).”
Background
Low Dopamine Function in Attention Deficit/Hyperactivity Disorder: Should Genotyping Signify Early Diagnosis in Children?
Gold, M., Blum, K., Oscar-Berman, M., & Braverman, E. (2014) · Postgraduate medicine · doi:10.3810/pgm.2014.01.2735 · Cited by 88 · see citing works
Self-citation
Adult ADHD and suicide
Furczyk, K., & Thome, J. (2014) · ADHD Attention Deficit and Hyperactivity Disorders · doi:10.1007/s12402-014-0150-1 · Cited by 99 · see citing works
Decision making in adults with ADHD
Mäntylä, T., Still, J., Gullberg, S., & Del Missier, F. (2012) · Journal of Attention Disorders · doi:10.1177/1087054709360494 · Cited by 84 · see citing works
“…several cognitive pathways that cause impairments of executive functions, including working memory, and response inhibition (e.g., Castellanos, Sonuga-Barke, Milham, & Tannock, 2006; Sonuga-Barke, 2003, 2005; see also Barkley, 1997; Blum et al., 2008; Casey, Getz, & Galvan, 2008; Steinberg, 2008).”
BackgroundResult
Vitamin D Status and Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Observational Studies.
Khoshbakht, Y., Bidaki, R., & Salehi-abargouei, A. (2018) · Advances in Nutrition · doi:10.1093/advances/nmx002 · Cited by 72 · see citing works
A chaotic model of sustaining attention problem in attention deficit disorder
Baghdadi, G., Jafari, S., Sprott, J. C., Towhidkhah, F., & Golpayegani, M. R. (2014) · Communications in Nonlinear Science and Numerical Simulation · doi:10.1016/j.cnsns.2014.05.015 · Cited by 76 · see citing works
“Every type of reward that has been studied and also stressful situations increase the level of dopamine transmission in the brain [35,36].”
Background
Attention-Deficit/Hyperactivity Disorder and Adverse Health Outcomes in Adults
Spencer, T. J., Faraone, S. V., Tarko, L., McDermott, K. M., & Biederman, J. (2014) · The Journal of Nervous and Mental Disease · doi:10.1097/nmd.0000000000000191 · Cited by 75 · see citing works
“…ADHD-related causal factors for adverse health indicators include a) a defective satiety feedback mechanism leading to an overweight condition (Blum et al., 2008), b) lower levels of omega-3 polyunsaturated fatty acids and high omega-6/ omega-3 fatty acid ratios increasing the risk for both…”
Background
Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders
Kiss, B., Laszlovszky, I., Krámos, B., Visegrády, A., Bobok, A. Á., Lévay, G. I., Lendvai, B., & Román, V. (2021) · Biomolecules · doi:10.3390/biom11010104 · Cited by 74 · see citing works
“Diseases such as schizophrenia [5], Parkinson’s disease (PD) [6], attention deficit hyperactive disorder [7], depression [8], addiction [9], restless leg syndrome (RLS) [10] and pituitary tumors [11] are all related to the disbalance of the dopaminergic system.”
Background
Sugar consumption and attention-deficit/hyperactivity disorder (ADHD): A birth cohort study
Del‐Ponte, B., Anselmi, L., Assunção, M. C. F., Tovo‐Rodrigues, L., Munhoz, T. N., Matijasevich, A., Rohde, L. A., & Santos, I. S. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2018.09.051 · Cited by 68 · see citing works
Overflow movements and white matter abnormalities in ADHD
D’Agati, E., Casarelli, L., Pitzianti, M. B., & Pasini, A. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.01.013 · Cited by 69 · see citing works
“There is increased interest in ADHD as a heritable neuropsychiatric condition linked to the pathogenesis of brain dopamine (Blum et al., 2008).”
Attention-deficit/hyperactivity disorder and eating disorders across the lifespan: A systematic review of the literature
Levin, R. L., & Rawana, J. S. (2016) · Clinical Psychology Review · doi:10.1016/j.cpr.2016.09.010 · Cited by 64 · see citing works
A literature review of dopamine in binge eating
Yu, Y. H., Miller, R. M., & Groth, S. W. (2022) · Journal of Eating Disorders · doi:10.1186/s40337-022-00531-y · Cited by 85 · see citing works
“Because individuals with depression and post-traumatic stress disorder usually have diminished dopamine function [87, 88], and those with childhood abuse usually have elevated dopamine function [89], the inclusion of people with these comorbidities may bias the results.”
Background
Effects of game-based digital therapeutics on attention deficit hyperactivity disorder in children and adolescents as assessed by parents or teachers: a systematic review and meta-analysis
Oh, S., Choi, J., Han, D. H., & Kim, E. (2024) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-023-02174-z · Cited by 63 · see citing works
ADHD pathogenesis in the immune, endocrine and nervous systems of juvenile and maturating SHR and WKY rats
Kozłowska, A., Wojtacha, P., Równiak, M., Kolenkiewicz, M., & Huang, A. C. W. (2019) · Psychopharmacology · doi:10.1007/s00213-019-5180-0 · Cited by 63 · see citing works
“Moreover, there are many studies reporting that administration of IL-1β and IL-6 in rodents reduced the level of dopamine in the brain (Zalcman et al. 1994; Anisman et al. 1996), similar to ADHD patients (Blum et al. 2008).”
BackgroundInfluential
Screen-exposure and altered brain activation related to attention in preschool children: An EEG study
Zivan, M., Bar, S., Xiang, J., Hutton, J., Farah, R., & Horowitz‐Kraus, T. (2019) · Trends in Neuroscience and Education · doi:10.1016/j.tine.2019.100117 · Cited by 59 · see citing works
Influence of attention-deficit/hyperactivity disorder on binge eating behaviors and psychiatric comorbidity profile of obese women
Nazar, B. P., Suwwan, R., Pinna, C. M. D. S., Duchesne, M., de Freitas, S. R., Sergeant, J. A., & Mattos, P. (2013) · Comprehensive Psychiatry · doi:10.1016/j.comppsych.2013.09.015 · Cited by 59 · see citing works
“Evidence of RDS has been shown in obese [41], ADHD [42], and SUD patients [43].”
Background
Acute Intravenous Synaptamine Complex Variant KB220™ “Normalizes” Neurological Dysregulation in Patients during Protracted Abstinence from Alcohol and Opiates as Observed Using Quantitative Electroencephalographic and Genetic Analysis for Reward Polymorphisms: Part 1, Pilot Study with 2 Case Reports
Miller, D. K., Bowirrat, A., Manka, M., Miller, M., Stokes, S., Manka, D., Allen, C., Gant, C. E., Downs, B. W., Smolen, A., et al. (2010) · Postgraduate Medicine · doi:10.3810/pgm.2010.11.2236 · Cited by 57 · see citing works
Self-citation
Treatment Considerations in Internet and Video Game Addiction
Greenfield, D. N. (2018) · Child and Adolescent Psychiatric Clinics of North America · doi:10.1016/j.chc.2017.11.007 · Cited by 57 · see citing works
Nanoplasmonic aptasensor for sensitive, selective, and real-time detection of dopamine from unprocessed whole blood
Biswas, A., Lee, S., Cencillo‐Abad, P., Karmakar, M., Patel, J., Soudi, M., & Chanda, D. (2024) · Science Advances · doi:10.1126/sciadv.adp7460 · Cited by 54 · see citing works
Structural and Functional Brain Abnormalities in Internet Gaming Disorder and Attention-Deficit/Hyperactivity Disorder: A Comparative Meta-Analysis
Gao, X., Zhang, M., Yang, Z., Wen, M., Huang, H., Zheng, R., Wang, W., Wei, Y., Cheng, J., Han, S., et al. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.679437 · Cited by 51 · see citing works
“(23) showed that ADHD is a reward deficiency disorder, and some theories considered that reward deficiency might predispose individuals to addictive, impulsive, and compulsive behavior.”
Background
Neuroinflammation as a possible link between attention-deficit/hyperactivity disorder (ADHD) and pain
Kerekes, N., Sánchez‐Pérez, A. M., & Landry, M. (2021) · Medical Hypotheses · doi:10.1016/j.mehy.2021.110717 · Cited by 49 · see citing works
No Change of Sleep After 6 and 12 Months of Methadone Maintenance Treatment
Peles, E., Schreiber, S., Hamburger, R. B., & Adelson, M. (2010) · Journal of Addiction Medicine · doi:10.1097/adm.0b013e3181e8b6c4 · Cited by 48 · see citing works
“This increment in weight may probably relate to the Reward Deficiency Syndrome (RDS) that characterizes drug addicts (Blum et al., 2008) before the addiction and that may even deteriorate during the chronic substance use and abuse and pathologically alters further the reward set point in a manner that individual may l…”
Background
Dopaminergic Modulation of Synaptic Plasticity, Its Role in Neuropsychiatric Disorders, and Its Computational Modeling
Asl, M. M., Vahabie, A., & Valizadeh, A. (2018) · Basic and Clinical Neuroscience Journal · doi:10.32598/bcn.9.10.125 · Cited by 48 · see citing works
“It is shown that damage in DA neurons of the VTA can be the cause of hyperactivity and substandard response to stress (Blum et al., 2008).”
Background
Associations among ADHD, Abnormal Eating and Overweight in a non-clinical sample of Asian children
Tong, L., Shi, H., & Li, X. (2017) · Scientific Reports · doi:10.1038/s41598-017-03074-4 · Cited by 46 · see citing works
Functional Neuroimaging Evidence for Distinct Neurobiological Pathways in Attention-Deficit/Hyperactivity Disorder
Stevens, M. C. G., Pearlson, G. D., Calhoun, V. D., & Bessette, K. L. (2017) · Biological Psychiatry Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2017.09.005 · Cited by 47 · see citing works
Women with ADHD: It is an explanation, not the excuse du jour
Waite, R. (2010) · Perspectives In Psychiatric Care · doi:10.1111/j.1744-6163.2010.00254.x · Cited by 43 · see citing works
“Individuals affected with ADHD have at least one target gene, the dopamine receptor D2 (DRD2) gene, which makes it difficult for neurons to respond to dopamine (Blum et al., 2008).”
BackgroundSelf-citation
Putative dopamine agonist (KB220Z) attenuates lucid nightmares in PTSD patients: Role of enhanced brain reward functional connectivity and homeostasis redeeming joy
McLaughlin, T., Blum, K., Oscar‐Berman, M., Febo, M., Agan, G., Fratantonio, J. L., Simpatico, T. A., & Gold, M. S. (2015) · Journal of Behavioral Addictions · doi:10.1556/2006.4.2015.008 · Cited by 44 · see citing works
“Following 27 clinical trials with KB220 variants, since 1982, there is strong evidence that this complex, which was designed to mimic the “Brain Reward Cascade”, appears to increase dopamine release and activation across the Brain Reward Circuitry leading dopamine homeostasis (Blum et al., 2008).”
MethodSelf-citation
Internet Addiction and Attention Deficit Hyperactivity Disorder Among Schoolchildren.
Weinstein, A. M., Yaacov, Y., Manning, M., Danon, P., & Weizman, A. (2015) · PubMed · Cited by 44 · see citing works
Dopamine in the Regulation of Glucose Homeostasis, Pathogenesis of Type 2 Diabetes, and Chronic Conditions of Impaired Dopamine Activity/Metabolism: Implication for Pathophysiological and Therapeutic Purposes
Lisco, G., Tullio, A. D., Iovino, M., Disoteo, O., Guastamacchia, E., Giagulli, V. A., & Triggiani, V. (2023) · Biomedicines · doi:10.3390/biomedicines11112993 · Cited by 44 · see citing works
Neuro-chemical activation of brain reward meso-limbic circuitry is associated with relapse prevention and drug hunger: A hypothesis
Blum, K., & Gold, M. S. (2011) · Medical Hypotheses · doi:10.1016/j.mehy.2011.01.005 · Cited by 42 · see citing works
Self-citation
Study of internet addiction in children with attention-deficit hyperactivity disorder and normal control
Singh, S., Rupesh, E., Adgaonkar, G., Subramanyam, A. A., & Kamath, R. M. (2018) · Industrial Psychiatry Journal · doi:10.4103/ipj.ipj_47_17 · Cited by 42 · see citing works
“[25] In addition, excessive Internet usage is maintained over a long period through stimulatory effects on reward and sensitization as ADHD children are hypothesized to have low dopamine availability in the brain reward system, which is overcome to an extent by dopamine secreted at reward center following the instant…”
Background
Highly sensitive and selective detection of dopamine using overoxidized polypyrrole/sodium dodecyl sulfate-modified carbon nanotube electrodes
Eom, G., Oh, C., Moon, J., Kim, H., Kim, M. K., Kim, K., Seo, J., Kang, T., & Lee, H. J. (2019) · Journal of Electroanalytical Chemistry · doi:10.1016/j.jelechem.2019.113295 · Cited by 41 · see citing works
The effects of early life stress on impulsivity
Sanchez, E. O., & Bangasser, D. A. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104638 · Cited by 40 · see citing works
The contribution of ADHD and attachment difficulties to online pornography use among students
Niazof, D., Weizman, A., & Weinstein, A. M. (2019) · Comprehensive Psychiatry · doi:10.1016/j.comppsych.2019.07.002 · Cited by 38 · see citing works
Serum levels of interleukin-6 and tumor necrosis factor alpha in children with attention-deficit hyperactivity disorder
shorbagy, H. H. E., Elsadek, A., Al-shokary, A. H., Abdelghani, W. E., Kamal, N. M., Ibrahim, A., Suliman, H. A., Barseem, N. F., Maksoud, Y. H. A., Azab, S. M., et al. (2020) · Journal of Pediatric Neurosciences · doi:10.4103/jpn.jpn_1_20 · Cited by 38 · see citing works
Facile chemical modification of Nb2CTx MXene with ethylene diamine for sensitive electrochemical detection of dopamine from human serum samples
Ankitha, M., Shabana, N., Arjun, A. M., & Rasheed, P. A. (2022) · Carbon Trends · doi:10.1016/j.cartre.2022.100232 · Cited by 38 · see citing works
Pharmacogenetics of naltrexone and disulfiram in alcohol dependent, dually diagnosed veterans
Arias, A. J., Gelernter, J. E., Gueorguieva, R. V., Ralevski, E., & Petrakis, I. L. (2014) · American Journal on Addictions · doi:10.1111/j.1521-0391.2014.12102.x · Cited by 37 · see citing works
A Systematic Review of Pharmacological Treatments for Internet Gaming Disorder
de Sá, R. R. C., Coelho, S. G., Parmar, P. K., Johnstone, S., Kim, H. S. A., & Tavares, H. (2023) · Psychiatry Investigation · doi:10.30773/pi.2022.0297 · Cited by 35 · see citing works
Relationship between attention-deficit hyperactivity disorder symptoms and problem gambling: A mediation analysis of influential factors among 7,403 individuals from the UK
Jacob, L., Haro, J. M., & Koyanagi, A. (2018) · Journal of Behavioral Addictions · doi:10.1556/2006.7.2018.72 · Cited by 36 · see citing works
“DOI: 10.1556/2006.7.2018.72 First published online August 25, 2018 Unauthenticated | Downloaded 07/15/21 08:52 AM UTC dysfunctions in the dopaminergic system (Blum et al., 2008; Ludolph et al., 2008) have been suggested.”
BackgroundInfluential
Social withdrawal and gambling-like profile after lentiviral manipulation of DAT expression in the rat accumbens
Adriani, W., Boyer, F., Leo, D., Canese, R., Podo, F., Perrone‐Capano, C., Dreyer, J., & Giovanni Laviola, A. (2010) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145709991210 · Cited by 34 · see citing works
“Thus, these rats may be proposed as a model for social problems, e.g. conduct disorder, often observed among ADHD patients (Blum et al. 2000, 2008).”
Background
Natural Product-Derived Treatments for Attention-Deficit/Hyperactivity Disorder: Safety, Efficacy, and Therapeutic Potential of Combination Therapy
Ahn, J. C., Ahn, H. S., Cheong, J. H., & Peña, I. D. (2016) · Neural Plasticity · doi:10.1155/2016/1320423 · Cited by 33 · see citing works
“Deficiency in GABA causes anxiety, restlessness, and obsessive behavior, symptoms often seen in ADHD [58].”
Background
A mechanistic model of ADHD as resulting from dopamine phasic/tonic imbalance during reinforcement learning
Véronneau-Veilleux, F., Robaey, P., Ursino, M., & Nekka, F. (2022) · Frontiers in Computational Neuroscience · doi:10.3389/fncom.2022.849323 · Cited by 32 · see citing works
“ADHD patients are vulnerable to drug dependence, which may be explained by an overlap of ADHD with the dopamine deficiency syndrome (Blum et al., 2008).”
Background
Using the Neuroadaptagen KB200z™ to Ameliorate Terrifying, Lucid Nightmares in RDS Patients: the Role of Enhanced, Brain-Reward, Functional Connectivity and Dopaminergic Homeostasis
McLaughlin, T., Blum, K., Oscar‐Berman, M., Febo, M., Demetrovics, Z., Agan, G., Fratantonio, J. L., & Gold, M. S. (2015) · Journal of Reward Deficiency Syndrome · doi:10.17756/jrds.2015-006 · Cited by 32 · see citing works
“Following 28 clinical trials with KB220 variants, since 1982; there is strong evidence that this complex, which was designed to mimic the “Brain Reward Cascade,” appears to increase dopamine release and activation across the Brain Reward Circuitry [34].”
MethodSelf-citation
Hyperfocus symptom and internet addiction in individuals with attention-deficit/hyperactivity disorder trait
Ishii, S., Takagi, S., Kobayashi, N., Jitoku, D., Sugihara, G., & Takahashi, H. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1127777 · Cited by 28 · see citing works
“Addition to it, Hyperfocus might play a role in developing internet addiction by activating the brain’s reward center and triggering the release of dopamine (48).”
Background
Offspring neuroimmune consequences of maternal malnutrition: Potential mechanism for behavioral impairments that underlie metabolic and neurodevelopmental disorders
Smith, B. L., & Reyes, T. M. (2017) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2017.07.007 · Cited by 30 · see citing works
“Hallmark features of these disorders include deficits in prefrontal executive control and reward processing (Aron and Poldrack, 2005; Blum et al., 2008; Brisch, 2014; Happé et al., 2006; Kriete and Noelle, 2015; Orellana and Slachevsky, 2013; Previc, 2006; Schachar et al., 1993; Weinberger, 1987).”
Background
Acute and chronic methylphenidate alters prefrontal cortex neuronal activity recorded from freely behaving rats
Salek, R., Claussen, C. M., Péez, A., & Dafny, N. (2012) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2012.01.009 · Cited by 33 · see citing works
“The PFC has pyramidal neurons with a high density of D1 like dopamine receptors and fewer D2 receptors, MPD administration results in increased dopamine activity in the PFC (Blum et al, 2008).”
Background
Alcohol and the Brain–Gut Axis: The Involvement of Microglia and Enteric Glia in the Process of Neuro-Enteric Inflammation
Khan, M. A. S., & Chang, S. L. (2023) · Cells · doi:10.3390/cells12202475 · Cited by 28 · see citing works
Untitled work
(2016) · PubMed · Cited by 28 · see citing works
Self-citation
A novel role for the ADHD risk gene latrophilin-3 in learning and memory in Lphn3 knockout rats
Regan, S. L., Pitzer, E. M., Wendel, J. R. H., Sugimoto, C., Williams, M. T., & Vorhees, C. V. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105456 · Cited by 27 · see citing works
“ADHD is thought to be the result of DA hypofunction with compensatory increases in DA release [64].”
High-fat diet-induced dopaminergic dysregulation induces REM sleep fragmentation and ADHD-like behaviors
Kang, J., Park, M. K., Oh, C., & Kim, T. (2023) · Psychiatry Research · doi:10.1016/j.psychres.2023.115412 · Cited by 27 · see citing works
A Shared Molecular and Genetic Basis for Food and Drug Addiction
Gold, M. S., Badgaiyan, R. D., & Blum, K. (2015) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2015.05.011 · Cited by 27 · see citing works
Self-citation
Epigenetic and Neural Circuitry Landscape of Psychotherapeutic Interventions
Miller, C. W. T. (2017) · Psychiatry Journal · doi:10.1155/2017/5491812 · Cited by 24 · see citing works
“Within the spectrum of psychopathology, control individuals with impulsive traits [182], as well as individuals with psychiatric diagnoses predisposing them to impulsive actions, such as ADHD, have shown heightened reward sensitivity and VS response to incentives [183, 184].”
Background
Enhanced ADHD classification through deep learning and dynamic resting state fMRI analysis
Firouzi, M., Kazemi, K., Ahmadi, M., Helfroush, M. S., & Aarabi, A. (2024) · Scientific Reports · doi:10.1038/s41598-024-74282-y · Cited by 24 · see citing works
Synchronous Fe3+-Enhanced Colorimetric and Liquid SERS-Based Detection of Dopamine Using Core–Shell Plasmonic Nanoparticles
Le, T. V., Park, J., & Lee, S. (2023) · ACS Applied Nano Materials · doi:10.1021/acsanm.3c00454 · Cited by 23 · see citing works
Effects of taurine on striatal dopamine transporter expression and dopamine uptake in SHR rats
Chen, V. C., Chiu, C., Chen, L., Hsu, T., & Tzang, B. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2018.04.031 · Cited by 22 · see citing works
“To the best of our knowledge, loss of dopamine is the most important cause of ADHD [35].”
Chronic passive exposure to aggression decreases D2 and 5-HT1B receptor densities
Suzuki, H., Han, S. D., & Lucas, L. (2010) · Physiology & Behavior · doi:10.1016/j.physbeh.2010.01.018 · Cited by 21 · see citing works
“Dopamine D2 receptors in the Acb are involved in not only aggressive behavior but also other reward-related behaviors, such as hyperactivity [63], sexual behavior [64], and drug abuse [65].”
Background
Reward Deficiency Syndrome: Attentional/Arousal Subtypes, Limitations of Current Diagnostic Nosology, and Future Research
Modestino, E. J., Blum, K., Oscar‐Berman, M., Gold, M. S., Duane, D. D., Sultan, S., & Auerbach, S. H. (2015) · Journal of Reward Deficiency Syndrome · doi:10.17756/jrds.2015-002 · Cited by 22 · see citing works
“Interactions in brain reward regions associated with RDS [Adapted from Blum et al. (2008)] [16] (1a.) Hypothalamus: Serotonin indirectly activates opiate receptors, causing a release of enkephalins in the ventral tegmental area (VTA).”
BackgroundSelf-citation
Adolescent behavioral and neural reward sensitivity: a test of the differential susceptibility theory
Richards, J. S., Vásquez, A. A., von Rhein, D. T., van der Meer, D., Franke, B., Hoekstra, P. J., Heslenfeld, D. J., Oosterlaan, J., Faraone, S. V., Buitelaar, J. K., et al. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.37 · Cited by 20 · see citing works
Impact of a Common Genetic Variation Associated With Putamen Volume on Neural Mechanisms of Attention-Deficit/Hyperactivity Disorder
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Functional Connectivity of Child and Adolescent Attention Deficit Hyperactivity Disorder Patients: Correlation with IQ
Park, B., Hong, J., Lee, S.-H., & Park, H. (2016) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2016.00565 · Cited by 19 · see citing works
Neural response during anticipation of monetary loss is elevated in adult attention deficit hyperactivity disorder
Wilbertz, G., Delgado, M. R., Tebartz Van Elst, L., Maier, S., Philipsen, A., & Blechert, J. (2017) · The World Journal of Biological Psychiatry · doi:10.3109/15622975.2015.1112032 · Cited by 18 · see citing works
“result in compensatory higher reward seeking (Blum et al. 2008).”
New developments on the neurobiological and pharmaco-genetic mechanisms underlying internet and videogame addiction
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Clinical Considerations in Internet and Video Game Addiction Treatment
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Is there a link between treatments with exogenous corticosteroids and dog behaviour problems?
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Processed Food–Sweets Patterns and Related Behaviors with Attention Deficit Hyperactivity Disorder among Children: A Case–Control Study
Yan, W. S., Lin, S., Wu, D., Shi, Y., Dou, L.-H., & Li, X. (2023) · Nutrients · doi:10.3390/nu15051254 · Cited by 17 · see citing works
“In addition, sugar-rich foods could trigger the reward system [24,25], and neuroimaging studies suggest that the neurobiological mechanisms of ADHD involve reward system dysfunction [26,27].”
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Underlying decision making processes on Iowa Gambling Task
Kumar, R., Kumar, K. J., & Benegal, V. (2018) · Asian Journal of Psychiatry · doi:10.1016/j.ajp.2018.12.006 · Cited by 17 · see citing works
The prefrontal cortex and the caudate nucleus respond conjointly to methylphenidate (Ritalin). Concomitant behavioral and neuronal recording study
Venkataraman, S. S., Claussen, C. M., Kharas, N., & Dafny, N. (2020) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2019.10.009 · Cited by 17 · see citing works
A New Paradigm for Training Hyperactive Dopamine Transporter Knockout Rats: Influence of Novel Stimuli on Object Recognition
Kurzina, N. P., Volnova, A. B., Aristova, I., & Gainetdinov, R. R. (2021) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2021.654469 · Cited by 17 · see citing works
Relationship between Symptoms of Disruptive Behavior Disorders and Unsafe Internet Usage in Early Adolescence
Vural, P., Uncu, Y., & Kılıç, E. Z. (2015) · Nöro Psikiyatri Arşivi · doi:10.5152/npa.2015.7346 · Cited by 16 · see citing works
Attention-Deficit/Hyperactivity Disorder Animal Model Presents Retinal Alterations and Methylphenidate Has a Differential Effect in ADHD versus Control Conditions
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“One of the hypotheses for ADHD etiology relies on the impairment in the dopaminergic system [41,42], and it is well established that dopamine plays a critical role in retinal function [43].”
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Safety, tolerability and pharmacokinetics of 2‐pyridylacetic acid, a major metabolite of betahistine, in a phase 1 dose escalation study in subjects with ADHD
Moorthy, G., Sallee, F. R., Gabbita, S. P., Zemlan, F. P., Sallans, L., & Desai, P. B. (2015) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.1955 · Cited by 16 · see citing works
Laminin α2 controls mouse and human stem cell behaviour during midbrain dopaminergic neuron development
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“A dopamine imbalance in the VTA mDA neurons has been implicated in the aetiology of ADHD, obsessive-compulsive disorder, addiction and schizophrenia (Blum et al., 2008; Grace, 2016; Nutt et al., 2015).”
Background
The Association between Excessive Internet Gaming Behavior and Immersive Tendency, Mediated by Attention Deficit/Hyperactivity Disorder Symptoms, in Korean Male University Students
Jung, D., Shim, E., Hyeonggyu, P., Lee, K., Lee, S., Kim, E., Chang, J. S., Jeong, S.-H., Kim, Y., Ahn, Y. M., et al. (2020) · Psychiatry Investigation · doi:10.30773/pi.2019.0173 · Cited by 15 · see citing works
Neurogenetic and Epigenetic Aspects of Cannabinoids
Dennen, C. A., Blum, K., Bowirrat, A., Khalsa, J. H., Thanos, P. K., Baron, D. A., Badgaiyan, R. D., Gupta, A., Braverman, E. R., & Gold, M. S. (2022) · Epigenomes · doi:10.3390/epigenomes6030027 · Cited by 16 · see citing works
“In addition, another subset of RDS is schizophrenia [28].”
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Delusion-proneness displays comorbidity with traits of autistic-spectrum disorders and ADHD
Louzolo, A., Gustavsson, P. J., Tigerström, L., Ingvar, M., Olsson, A., & Petrović, P. (2017) · PLoS ONE · doi:10.1371/journal.pone.0177820 · Cited by 15 · see citing works
Let’s Talk about Sex… and ADHD: Findings from an Anonymous Online Survey
Young, S., Klassen, L. J., Reitmeier, S. D., Matheson, J. D., & Gudjonsson, G. H. (2023) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph20032037 · Cited by 17 · see citing works
“One possible explanation may be greater general reward deficiency in people with ADHD [29].”
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Efficacy of Photobiomodulation for Attention Deficit Hyperactivity Disorder (ADHD): Case Studies
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Case report: Methylphenidate improved chronic pain in an adult patient with attention deficit hyperactivity disorder
Zain, E., Sugimoto, A., Egawa, J., & Someya, T. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1091399 · Cited by 14 · see citing works
“In ADHD patients, MPH improves the hypodopaminergic state of the PFC and limbic system (53) and increases DA activity in the parietal cortex, PFC, and striatum, which regulate cognitive functions (54, 55).”
Background
Prevalence of and factors contributing to glue sniffing in the South Asian Association for Regional Cooperation (SAARC) region: a scoping review and meta-analysis
Munawar, K., Choudhry, F. R., Hadi, M. A., & Khan, T. M. (2020) · Substance Use & Misuse · doi:10.1080/10826084.2019.1701036 · Cited by 13 · see citing works
“There is a greater probability of illegal drug use in children who have attention deficit hyperactivity disorder (ADHD) tendencies (Blum et al., 2008; Ellenhorn, 1997).”
Background

Neurogenetic Impairments of Brain Reward Circuitry Links to Reward Deficiency Syndrome (RDS): Potential Nutrigenomic Induced Dopaminergic Activation
Oscar‐Berman, M. (2012) · Journal of Genetic Syndromes & Gene Therapy · doi:10.4172/2157-7412.1000e115 · Cited by 34 · see citing works
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Reward deficiency syndrome: genetic aspects of behavioral disorders
Comings, D. E., & Blum, K. (2000) · Progress in Brain Research · doi:10.1016/s0079-6123(00)26022-6 · Cited by 621 · see citing works
Self-citation
The Reward Deficiency Syndrome: A Biogenetic Model for the Diagnosis and Treatment of Impulsive, Addictive and Compulsive Behaviors
Blum, K., Braverman, E. R., Holder, J. M., Lubar, J. F., Monastra, V. J., Miller, D., Lubar, J. O., Chen, T. J. H., & Comings, D. E. (2000) · Journal of Psychoactive Drugs · doi:10.1080/02791072.2000.10736099 · Cited by 977 · see citing works
Self-citation
Neurogenetics and Nutrigenomics of Reward Deficiency Syndrome (RDS): Stratification of Addiction Risk and Mesolimbic Nutrigenomic Manipulation of Hypodopaminergic Function
Blum, K., Han, D. C., Giordano, J., Lohmann, R., Braverman, E. R., Madigan, M. A., Barh, D., Femino, J., Hauser, M., Downs, B. W., et al. (2013) · Springer eBooks · doi:10.1007/978-81-322-1184-6_18 · Cited by 3 · see citing works
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Dopamine Genetics and Function in Food and Substance Abuse
Blum, K. (2013) · Journal of Genetic Syndromes & Gene Therapy · doi:10.4172/2157-7412.1000121 · Cited by 51 · see citing works
Self-citation

Authors: Oscar Berman, M., Blum, K., Chen, T. J., Braverman, E., Waite, R., Downs, W., Arcuri, V., Notaro, A., Palomo, T., & Comings
Affiliations: Wake Forest University Health Sciences (US)
Weill Cornell Medicine (US)
City Of Hope National Medical Center (US)
Chang Jung Christian University (TW)
ORCID: Braverman, Eric
Venue: Neuropsychiatric Disease and Treatment
Publisher: Informa UK Limited
Published: 2008-11
Volume: 4
Issue: 5
Pages: 893
ISSN: 1176-6328 (ISSN-L)
DOI: 10.2147/ndt.s2627
PMC: PMC2626918
OpenAlex: W2027531652
Cited by: 248
References: 111
Citations by year: 2026: 3 · 2025: 23 · 2024: 30 · 2023: 31 · 2022: 21 · 2021: 20 · 2020: 11 · 2019: 9 · 2018: 15 · 2017: 15 · 2016: 13 · 2015: 16 · 2014: 8 · 2013: 7 · 2012: 6
FWCI: 4.68
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc
Locations: Neuropsychiatric Disease and Treatment (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
OpenBU (Boston University) (submittedVersion)
Funders: U.S. Department of Health and Human Services
U.S. Department of Veterans Affairs
National Institute on Alcohol Abuse and Alcoholism (R01 AA07112, K05AA00219, R01-AA07112 and K05-AA00219, R01AA007112, K05AA000219)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords: attention deficit hyperactivity disorder, reward deficiency syndrome, dopaminergic system, dopaminergic genes, genetic polymorphism, drug-seeking behavior, addiction, compulsive behavior, nutraceuticals, early diagnosis, ADHD subtypes

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Attention-deficit-hyperactivity disorder and reward deficiency syndrome

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