Reward Deficiency Syndrome (RDS) Surprisingly Is Evolutionary and Found Everywhere: Is It "Blowin' in the Wind"?

doi:10.3390/jpm12020321

. 2022 Feb 21;12(2):321.

doi: 10.3390/jpm12020321.

Reward Deficiency Syndrome (RDS) Surprisingly Is Evolutionary and Found Everywhere: Is It "Blowin' in the Wind"?

Kenneth Blum^{1

2

3

4

5}, Thomas McLaughlin⁶, Abdalla Bowirrat⁷, Edward J Modestino⁸, David Baron¹, Luis Llanos Gomez³, Mauro Ceccanti⁹, Eric R Braverman³, Panayotis K Thanos^{10

11}, Jean Lud Cadet¹², Igor Elman^{13

14}, Rajendra D Badgaiyan^{15

16}, Rehan Jalali³, Richard Green³, Thomas A Simpatico⁴, Ashim Gupta¹⁷, Mark S Gold¹⁸

Affiliations

¹ Division of Addiction Research & Education, Center for Psychiatry, Medicine, & Primary Care (Office of the Provost), Graduate College, Western University of Health Sciences, Pomona, CA 91766, USA.
² Institute of Psychology, ELTE Eötvös Loránd University, 1075 Budapest, Hungary.
³ Division of Nutrigenomics, The Kenneth Blum Behavioral Neurogenetic Institute, (Ivitalize, Inc.), Austin, TX 78701, USA.
⁴ Department of Psychiatry, University of Vermont, Burlington, VT 05405, USA.
⁵ Department of Psychiatry, Wright University Boonshoff School of Medicine, Dayton, OH 45324, USA.
⁶ Column Health Clinic, Lawrence, MA 01843, USA.
⁷ Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel 40700, Israel.
⁸ Department of Psychology, Curry College, Milton, MA 02186, USA.
⁹ Alcohol Addiction Program, Latium Region Referral Center, Sapienza University of Rome, 00185 Roma, Italy.
¹⁰ Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY 14203, USA.
¹¹ Department of Psychology, State University of New York at Buffalo, Buffalo, NY 14203, USA.
¹² Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
¹³ Center for Pain and the Brain (PAIN Group), Department of Anesthesiology, Critical Care & Pain Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
¹⁴ Cambridge Health Alliance, Harvard Medical School, Cambridge, MA 02139, USA.
¹⁵ Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, Long School of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA.
¹⁶ Department of Psychiatry, MT. Sinai School of Medicine, New York, NY 10003, USA.
¹⁷ Future Biologics, Lawrenceville, GA 30043, USA.
¹⁸ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.

PMID: 35207809
PMCID: PMC8875142
DOI: 10.3390/jpm12020321

Reward Deficiency Syndrome (RDS) Surprisingly Is Evolutionary and Found Everywhere: Is It "Blowin' in the Wind"?

Kenneth Blum et al. J Pers Med. 2022.

. 2022 Feb 21;12(2):321.

doi: 10.3390/jpm12020321.

Authors

Affiliations

¹ Division of Addiction Research & Education, Center for Psychiatry, Medicine, & Primary Care (Office of the Provost), Graduate College, Western University of Health Sciences, Pomona, CA 91766, USA.
² Institute of Psychology, ELTE Eötvös Loránd University, 1075 Budapest, Hungary.
³ Division of Nutrigenomics, The Kenneth Blum Behavioral Neurogenetic Institute, (Ivitalize, Inc.), Austin, TX 78701, USA.
⁴ Department of Psychiatry, University of Vermont, Burlington, VT 05405, USA.
⁵ Department of Psychiatry, Wright University Boonshoff School of Medicine, Dayton, OH 45324, USA.
⁶ Column Health Clinic, Lawrence, MA 01843, USA.
⁷ Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel 40700, Israel.
⁸ Department of Psychology, Curry College, Milton, MA 02186, USA.
⁹ Alcohol Addiction Program, Latium Region Referral Center, Sapienza University of Rome, 00185 Roma, Italy.
¹⁰ Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY 14203, USA.
¹¹ Department of Psychology, State University of New York at Buffalo, Buffalo, NY 14203, USA.
¹² Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
¹³ Center for Pain and the Brain (PAIN Group), Department of Anesthesiology, Critical Care & Pain Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
¹⁴ Cambridge Health Alliance, Harvard Medical School, Cambridge, MA 02139, USA.
¹⁵ Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, Long School of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA.
¹⁶ Department of Psychiatry, MT. Sinai School of Medicine, New York, NY 10003, USA.
¹⁷ Future Biologics, Lawrenceville, GA 30043, USA.
¹⁸ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.

PMID: 35207809
PMCID: PMC8875142
DOI: 10.3390/jpm12020321

Abstract

Reward Deficiency Syndrome (RDS) encompasses many mental health disorders, including a wide range of addictions and compulsive and impulsive behaviors. Described as an octopus of behavioral dysfunction, RDS refers to abnormal behavior caused by a breakdown of the cascade of reward in neurotransmission due to genetic and epigenetic influences. The resultant reward neurotransmission deficiencies interfere with the pleasure derived from satisfying powerful human physiological drives. Epigenetic repair may be possible with precision gene-guided therapy using formulations of KB220, a nutraceutical that has demonstrated pro-dopamine regulatory function in animal and human neuroimaging and clinical trials. Recently, large GWAS studies have revealed a significant dopaminergic gene risk polymorphic allele overlap between depressed and schizophrenic cohorts. A large volume of literature has also identified ADHD, PTSD, and spectrum disorders as having the known neurogenetic and psychological underpinnings of RDS. The hypothesis is that the true phenotype is RDS, and behavioral disorders are endophenotypes. Is it logical to wonder if RDS exists everywhere? Although complex, "the answer is blowin' in the wind," and rather than intangible, RDS may be foundational in species evolution and survival, with an array of many neurotransmitters and polymorphic loci influencing behavioral functionality.

Keywords: Genetic Addiction Risk Severity (GARS) Test; dopamine; hypodopaminergia; pro-dopamine regulation (KB220).

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Conflict of interest statement

K.B. is the recipient of commissions derived from the GARS test and Restoregen, per license agreements. R.J. and R.G. are paid consultants of Ivitalize Inc. There are no more conflicts to declare. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

**Figure 1**
This cartoon figure illustrates some of the interactions of several neurotransmitter pathways in the Brain Reward Cascade (BRC) system. Environmental stimulation in the hypothalamus causes the release of serotonin, which, in turn, via, for example, 5HT-2a receptors activates (green equals sign) opioid peptides, releasing them into the hypothalamus. The opioid peptides have two distinct effects via two different opioid receptors. The first inhibits (red hash sign) through the mu-opioid receptor (possibly via enkephalin), which projects to the substantia nigra GABAA neurons, and the second stimulates (green equal sign) cannabinoid neurons (e.g., 2-archydonoglcerol and anandamide) through beta-endorphin-linked delta receptors, which, in substantia nigra, inhibit GABAA neurons. Activated cannabinoids, mostly 2-archydonoglcerol, can also disinhibit (red hash sign) substantia nigra GABAA neurons indirectly by activating G1/0-coupled CB1 receptors. Similarly, dorsal raphe nuclei (DRN) glutamate neurons can disinhibit substantia nigra GABAA neurons indirectly through the activation of GLU M3 receptors (red hash sign). Stimulated GABAA neurons will powerfully (red hash signs) inhibit VTA glutaminergic drive via GABAB 3 neurons. VTA glutamate neurons project to dopamine neurons through NMDA receptors (green equals sign), where they preferentially release dopamine at the nucleus accumbens, shown as a bullseye, indicating euphoria (a motivational response).

**Figure 2**
A schematic of RDS. This figure illustrates the categorization of RDS behaviors, showing which behaviors are addictive, impulsive, obsessive, and personality disorders. Sub-categories divide addictive behaviors into substance and non-substance related and impulsive into disruptive/impulsive and spectrum disorders. These behaviors have dopaminergic dysfunction in common: acute excess or chronic deficit of dopamine release in the brain reward circuitry.

**Figure 3**
Summary of RDS Phenotype. This illustrates the relationship between endophenotypes and phenotype in RDS (modified from [126]).

See this image and copyright information in PMC

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Evidence Based Clinical Analytics Supporting the Genetic Addiction Risk Severity (GARS) Assessment to Early Identify Probands in Preaddiction.
Blum K, Bowirrat A, Thanos PK, Hanna C, Khalsa J, Baron D, Elman I, Badgaiyan RD, Dennen C, Braverman ER, Carney P, Lewandrowski KU, Sharafshah A, Gold MS. Blum K, et al. EC Psychol Psychiatr. 2024 Dec 26;13(1):1-3. EC Psychol Psychiatr. 2024. PMID: 38298272 Free PMC article. No abstract available.
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"TO BE OR NOT TO BE" GWAS Ends the Controversy about the DRD2 Gene as a Determinant of Reward Deficiency Syndrome (RDS).
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References

1. Blum K., Noble E.P., Sheridan P.J., Montgomery A., Ritchie T., Jagadeeswaran P., Nogami H., Briggs A.H., Cohn J.B. Allelic association of human dopamine D2 receptor gene in alcoholism. JAMA. 1990;263:2055–2060. doi: 10.1001/jama.1990.03440150063027. - DOI - PubMed
1. Blum K., Gold M., Demetrovics Z., Archer T., Thanos P.K., Baron D., Badgaiyan R.D. Substance use disorder a bio-directional subset of reward deficiency syndrome. Front. Biosci. 2017;22:1534–1548. doi: 10.2741/4557. - DOI - PubMed
1. Blum K., Thanos P.K., Gold M.S. Dopamine and glucose, obesity, and reward deficiency syndrome. Front. Psychol. 2014;5:919. doi: 10.3389/fpsyg.2014.00919. - DOI - PMC - PubMed
1. Blum K. Reward Deficiency Syndrome. In: Wenzel A., editor. The Sage Encyclopedia of Abnormal Clinical Psychology. Sage Publications; Conshohocken, PA, USA: 2017.
1. Dawkins R. Should doctors be Darwinian? Trans. Med. Soc. Lond. 2002;119:15–30. - PubMed

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[1] Blum K., Noble E.P., Sheridan P.J., Montgomery A., Ritchie T., Jagadeeswaran P., Nogami H., Briggs A.H., Cohn J.B. Allelic association of human dopamine D2 receptor gene in alcoholism. JAMA. 1990;263:2055–2060. doi: 10.1001/jama.1990.03440150063027. - DOI - PubMed

[2] Blum K., Noble E.P., Sheridan P.J., Montgomery A., Ritchie T., Jagadeeswaran P., Nogami H., Briggs A.H., Cohn J.B. Allelic association of human dopamine D2 receptor gene in alcoholism. JAMA. 1990;263:2055–2060. doi: 10.1001/jama.1990.03440150063027. - DOI - PubMed

[3] Blum K., Gold M., Demetrovics Z., Archer T., Thanos P.K., Baron D., Badgaiyan R.D. Substance use disorder a bio-directional subset of reward deficiency syndrome. Front. Biosci. 2017;22:1534–1548. doi: 10.2741/4557. - DOI - PubMed

[4] Blum K., Gold M., Demetrovics Z., Archer T., Thanos P.K., Baron D., Badgaiyan R.D. Substance use disorder a bio-directional subset of reward deficiency syndrome. Front. Biosci. 2017;22:1534–1548. doi: 10.2741/4557. - DOI - PubMed

[5] Blum K., Thanos P.K., Gold M.S. Dopamine and glucose, obesity, and reward deficiency syndrome. Front. Psychol. 2014;5:919. doi: 10.3389/fpsyg.2014.00919. - DOI - PMC - PubMed

[6] Blum K., Thanos P.K., Gold M.S. Dopamine and glucose, obesity, and reward deficiency syndrome. Front. Psychol. 2014;5:919. doi: 10.3389/fpsyg.2014.00919. - DOI - PMC - PubMed

[7] Blum K. Reward Deficiency Syndrome. In: Wenzel A., editor. The Sage Encyclopedia of Abnormal Clinical Psychology. Sage Publications; Conshohocken, PA, USA: 2017.

[8] Blum K. Reward Deficiency Syndrome. In: Wenzel A., editor. The Sage Encyclopedia of Abnormal Clinical Psychology. Sage Publications; Conshohocken, PA, USA: 2017.

[9] Dawkins R. Should doctors be Darwinian? Trans. Med. Soc. Lond. 2002;119:15–30. - PubMed

[10] Dawkins R. Should doctors be Darwinian? Trans. Med. Soc. Lond. 2002;119:15–30. - PubMed

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Reward Deficiency Syndrome (RDS) Surprisingly Is Evolutionary and Found Everywhere: Is It "Blowin' in the Wind"?

Affiliations

Reward Deficiency Syndrome (RDS) Surprisingly Is Evolutionary and Found Everywhere: Is It "Blowin' in the Wind"?

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

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References

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