Should We Embrace Vaccines for Treating Substance- Related Disorder, A Subset of Reward Deficiency Syndrome (RDS)?

Kenneth Blum1-5*, Rajendra D. Badgaiyan6, Daniel H. Anges7,8 and Mark S. Gold9,10

1Department of Psychiatry & McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA
2Department of Neurology, PATH Foundation NY, NY, USA
3Department of Psychiatry, Human Integrated Services Unit, University of Vermont Center for Clinical & Translational Science, University of Vermont College of Medicine, Burlington, VT, USA
4Department of Addiction Research & Therapy, Malibu Beach Recovery Center, Malibu, CA, USA
5Division of Addiction Services, Dominion Diagnostics, LLC, North Kingston, RI, USA
6Department of Psychiatry, University of Minnesota College of Medicine, Minneapolis, MN, USA
7Department of Psychiatry and Behavioral Science, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
8Rivermend Health LLC, Atlanta, GA, USA
9Departments of Psychiatry & Behavioral Sciences at the Keck, University of Southern California, School of Medicine, CA, USA
10Director of Research, Drug Enforcement Administration (DEA) Educational Foundation, Washington, D.C., USA


To the Editor,

Undoubtedly substance-related disorder is a chronically relapsing problem worldwide, the question is; should anti-drug vaccines be embraced for treatment of this enormous problem?. The Federal Drug Administration (FDA) in the United States has approved a number of Medical Assisted Treatments (MAT) for alcohol, opiates and even Nicotine abuse, while, other abusable drugs like cocaine and cannabis have not been addressed [1]. Estimates place lifetime risks of transitioning from drug use to dependence from 8.9% to 67.5% [2]. Certainly there is strong evidence for inheritability of both substance and non-substance related seeking behaviors now under the Reward Deficiency Syndrome (RDS) rubric [3]. In fact using Bayesian theorem modeling, carriers born with a variant in the dopamine D2 receptor gene have a 74% predictive value to abuse drugs, food, and other process addictions close to the above estimate. However, Kendler et al. [4] suggested it to be somewhat lower at 50%. According to Belcher et al. [1] it is noteworthy that a number of studies have shown that striatal D2 receptor availability inversely correlates with measures of impulsive response in both animals and addicted humans [5].

Understanding the powerful role of dopamine in pleasure induction at mesolimbic and pre-frontal cortex loci, instead of embracing long-term homeostatic activation of dopaminergic function [6, 7] –MAT approval from the FDA has favored blocking dopamine release. Although it is understood that all drugs of abuse preferentially stimulate neuronal dopamine in important brain regions, because powerful D2 stimulation causes chronic D2 down-regulation there are no approved dopaminergic agonists [8]. In an attempt to overcome abuse of these dopaminergic activators, world class scientists have engaged in the development of potential antidrug vaccines [9] and have been quite successful in this important new research.

Vaccines work by inducing drug-specific antibodies in the bloodstream that prevent drug entry into the brain. The antibodies bind to the drug of abuse to create a molecule too large to enter the blood-brain barrier [10]. Many prominent laboratories, especially from Kosten’s group, have now developed vaccines with antibodies directed against cocaine [11], methamphetamine [12], and possibly phencyclidine. The anti-cocaine vaccine is now in clinical trials with limited success [13]. Others have pursued similar heroin hapten-BSA conjugated vaccines [14]. Importantly, Schlosburg et al. [15] found that an anti-heroin "Dynamic" vaccine blocks relapse to compulsive intake of heroin in rats. Unlike other types of vaccines, this "Dynamic" vaccine creates antibodies against heroin and its psychoactive metabolites by the presentation of multihaptenic structures that match heroin’s metabolism to the immune system. In addition, anti-nicotine vaccines have been developed recently [16]. Antinicotine vaccines showed promise in animal models [17], however when administered to human smokers did not lead to changes in brain activity during smoking cue exposure [18].

An underlying issue in all of this research is to deliver high concentrations of circulating drug-specific antibodies to attenuate drug-seeking and drug-taking behavior when the drug is repeatedly available, especially in high doses. The promise of the presentation of multihaptenic structures to potentially block even drug metabolites seems quite prudent, but must await human clinical trials. This accomplishment, likened in disruptive technology to the Polio vaccine from the early 1950s, could not have been achieved without advancements in immunology and increased knowledge of the molecular biology of substance abuse acquired through progress in neuro-imaging techniques. In fact, unpublished work, from one of us (KB) with Peter Sheridan at the University of Texas Health Science Center, in the mid 80’s attempted to utilize known haptens and available adjuncts to develop an anti-ethanol vaccine. While they found significant antibodies, it was not sufficient to block ethanol sleep time in mice.

The questions that remain amongst continued excitement and commitment to this endeavor as a viable treatment option for hardcore addicts that want to quit must be considered and vetted by the scientific community. Accordingly, Kantak [9] pointed out a number of potential problems.

1. There is no protection against drugs that are structurally dissimilar but produce the same effects as the drug of choice;

2. Antibody formation is tremendously variable;

3. Drug cravings that predispose addicts to relapse are not effected;

4. There are serious legal and ethical concerns related to forced or coerced vaccination; and

5. Vaccines are unsuitable for women of childbearing age.

We encourage the further development of this promising treatment option and applaud scientific exploration and the tremendous efforts made toward the advancement of antidrug abuse vaccines. We are, however, concerned that simply blocking the effects of the drug of choice, would fail to treat poly-drug abuse. It would also leave the hypodopaminergic trait (genetic) or state (epigenetic) untreated resulting in addiction transfer or other RDS behaviors such as food and process addictions as suggested by Blum et al. [19].

Scientists must initiate more clinical research into many options, especially for the long-term dopamine agonistic rather than antagonistic therapy [20-26]. Further research is required, and this worthwhile exploration must continue before we can embrace the use of anti-drug abuse vaccines in chemical dependency programs for the treatment of RDS.

The important work from NIDA and NIAAA and other addiction research institutions across the globe must be given very high priority if we are to combat addiction. RDS effects millions if not billions, like other chronic relapsing diseases that plague humans worldwide.

In summary, we are poised for major breakthroughs regarding potential anti-drug vaccines, however, unlike the poliomyelitis virus a singular disease antigen, the target of these vaccines is the specific molecular structures of the current drug of choice. The widespread utilization of anti-drug vaccines will be limited but may be a valuable adjunct to the treatment of RDS a complex disease subject to associated polygenetic and epigenetic interactions.

Acknowledgements

The authors appreciate the expert editorial assistance of Margaret A. Madigan.

Funding Sources

Kenneth Blum is the co-recipient of a grant from The Life Extension Foundation, Ft. Lauderdale, FL, USA to Path Foundation, NY, USA. Dr. Badgaiyan is supported by the National Institutes of Health grants 1R01NS073884 and 1R21MH073624, and VA Merit Review Awards CX000479 and CX000780.

Conflict of Interest

Kenneth Blum, PhD holds US and Foreign patents issued and pending on KB220Z and receives royalties based on its commercialization from various sources. Dr. Blum is also an officer and stock holder of IGENE, LLC, Victory Nutrition, RDSolutions, Inc. and is a paid consultant of Dominion Diagnostics, LLC, and Malibu Recovery Center. Dr. Blum is a member of the scientific advisory board of Dominion Diagnostics, LLC and a member of the Board of Directors of RDSolutions Inc. He also serves as Chief Scientific Advisor to Dominion Diagnostics, LLC and is currently the Chief Scientific Officer of RDSolutions, Inc. and Victory Nutrition International, LLC. DRs Gold and Anges are paid consultants of Rivermend Health, Atlanta Ga. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript part from those disclosed.

Authors Contribution

All the authors contributed equally.

References

1. Belcher AM, Volkow ND, Moeller FG, Ferré S. 2014. Personality traits and vulnerability or resilience to substance use disorders. Trends Cogn Sci 18(4): 211-217. doi: 10.1016/j.tics.2014.01.010

2. Lopez-Quintero C, Pérez de los Cobos J, Hasin DS, Okuda M, Wang S, et al. 2011. Probability and predictors of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drug Alcohol Depend 115(1-2): 120-130. doi: 10.1016/j.drugalcdep.2010.11.004

3. Blum K, Sheridan PJ, Wood RC, Braverman ER, Chen TJ, et al. 1996. The D2 dopamine receptor gene as a determinant of reward deficiency syndrome. J R Soc Med 89(7): 396-400. doi: 10.1177/014107689608900711

4. Kendler KS, Chen X, Dick D, Maes H, Gillespie N, et al. 2012. Recent advances in the genetic epidemiology and molecular genetics of substance use disorders. Nat Neurosci 15(2): 181-189. doi: 10.1038/nn.3018

5. Etkin A, Wager TD. 2007. Functional neuroimaging of anxiety: a metaanalysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry 164(10): 1476-1488. doi: 10.1176/appi.ajp.2007.07030504

6. Blum K, Chen AL, Chen TJ, Braverman ER, Reinking J, et al. 2008. Activation instead of blocking mesolimbic dopaminergic reward circuitry is a preferred modality in the long term treatment of reward deficiency syndrome (RDS): a commentary. Theor Biol Med Model 5: 24. doi: 10.1186/1742-4682-5-24

7. Blum K, Febo M, McLaughlin T, Cronjé FJ, Han D, et al. 2014. Hatching the behavioral addiction egg: Reward Deficiency Solution System (RDSS)™ as a function of dopaminergic neurogenetics and brain functional connectivity linking all addictions under a common rubric. J Behav Addict 3(3): 149-156. doi: 10.1556/JBA.3.2014.019

8. Dackis CA, Gold MS, Sweeney DR, Byron JP Jr, Climko R. 1987. Single-dose bromocriptine reverses cocaine craving. Psychiatry Res 20(4): 261-264. doi: 10.1016/0165-1781(87)90086-2

9. Kantak KM. 2003. Vaccines against drugs of abuse: a viable treatment option? Drugs 63(4): 341-352. doi: 10.2165/00003495-200363040-00001

10. Kinsey BM, Jackson DC, Orson FM. 2009. Anti-drug vaccines to treat substance abuse. Immunol Cell Biol 87(4): 309-314. doi: 10.1038/icb.2009.17

11. Orson FM, Wang R, Brimijoin S, Kinsey BM, Singh RA, et al. 2014. The future potential for cocaine vaccines. Expert Opin Biol Ther 14(9): 1271-1283. doi: 10.1517/14712598.2014.920319

12. Shen XY, Kosten TA, Lopez AY, Kinsey BM, Kosten TR, et al. 2013. A vaccine against methamphetamine attenuates its behavioral effects in mice. Drug Alcohol Depend 129(1-2): 41-48. doi: 10.1016/j.drugalcdep.2012.09.007

13. Kosten TR, Domingo CB, Shorter D, Orson F, Green C, et al. 2014. Vaccine for cocaine dependence: a randomized double-blind placebocontrolled efficacy trial. Drug Alcohol Depend 140: 42-47. doi: 10.1016/j.drugalcdep.2014.04.003

14. Torres OB, Jalah R, Rice KC, Li F, Antoline JF, et al. 2014. Characterization and optimization of heroin hapten-BSA conjugates: method development for the synthesis of reproducible hapten-based vaccines. Anal Bioanal Chem 406(24): 5927-5937. doi: 10.1007/s00216-014-8035-x

15. Schlosburg JE, Vendruscolo LF, Bremer PT, Lockner JW, Wade CL, et al. 2013. Dynamic vaccine blocks relapse to compulsive intake of heroin. Proc Natl Acad Sci USA 110(22): 9036-9041. doi: 10.1073/pnas.1219159110

16. Miller KD, Roque R, Clegg CH. 2014. Novel anti-nicotine vaccine using a trimeric coiled-coil hapten carrier. PLoS One 9(12): e114366. doi: 10.1371/journal.pone.0114366

17. Pravetoni M, Keyler DE, Raleigh MD, Harris AC, Lesage MG, et al. 2011. Vaccination against nicotine alters the distribution of nicotine delivered via cigarette smoke inhalation to rats. Biochem Pharmacol 81(9): 1164-1170. doi: 10.1016/j.bcp.2011.02.004

18. Havermans A, Vuurman EF, van den Hurk J, Hoogsteder P, van Schayck OC. 2014. Treatment with a nicotine vaccine does not lead to changes in brain activity during smoking cue exposure or a working memory task. Addiction 109(8): 1260-1267. doi: 10.1111/add.12577

19. Blum K, Bailey J, Gonzalez AM, Oscar-Berman M, Liu Y, et al. 2011. Neuro-genetics of Reward Deficiency Syndrome (RDS) as the root cause of "addiction transfer": a new phenomenon common after bariatric surgery. J Genet Syndr Gene Ther S2: 001. doi: 10.4172/2157-7412.S2-001

20. Blum K, Liu Y, Wang W, Wang Y, Zhang Y, et al. 2015. rsfMRI effects of KB220Z™ on neural pathways in reward circuitry of abstinent genotyped heroin addicts. Postgrad Med 127(2): 232-241.

21. Cui Y, Ostlund SB, James AS, Park CS, Ge W, et al. 2013. Targeted expression of μ-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward. Nat Neurosci 17(2): 254-261. doi: 10.1038/nn.3622

22. David SP, Strong DR, Leventhal AM, Lancaster MA, McGeary JE, et al. 2013. Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: results from two randomized clinical trials of bupropion. Addiction 108(12): 2202-2211. doi: 10.1111/add.12325

23. Kuhn J, Bührle CP, Lenartz D, Sturm V. 2013. Deep brain stimulation in addiction due to psychoactive substance use. Handb Clin Neurol 116: 259-269. doi: 10.1016/B978-0-444-53497-2.00021-8

24. Robson MJ, Noorbakhsh B, Seminerio MJ, Matsumoto RR. 2012. Sigma-1 receptors: potential targets for the treatment of substance abuse. Curr Pharm Des 18(7): 902-919. doi: 10.2174/138161212799436601

25. Filip M, Zaniewska M, Frankowska M, Wydra K, Fuxe K. 2012. The importance of the adenosine A(2A) receptor-dopamine D(2) receptor interaction in drug addiction. Curr Med Chem 19(3): 317-355. doi: 10.2174/092986712803414231

26. Blum K, Oscar-Berman M, Stuller E, Miller D, Giordano J, Morse S, et al. 2012. Neurogenetics and nutrigenomics of neuro-nutrient therapy for Reward Deficiency Syndrome (RDS): clinical ramifications as a function of molecular neurobiological mechanisms. J Addict Res Ther 3(5): 139. doi: 10.4172/2155-6105.1000139


*Correspondence to:

Kenneth Blum, PhD, DHL
Department of Psychiatry and McKnight Brain Institute
University of Florida College of Medicine
Box 100183 Gainesville, FL, 32610-0183, USA
Tel: +1-352-392-6680
Fax: +1-352-392-8217
E-mail: drd2gene@ufl.edu

Received: January 15, 2015
Accepted: January 27, 2015
Published: January 29, 2015

Citation: Blum K, Badgaiyan RD, Anges DH, Gold MS. 2015. Should We Embrace Vaccines for Treating Substance-Related Disorder, A Subset of Reward Deficiency Syndrome (RDS)? J Reward Defic Syndr 1(1): 3-5.

Copyright: © Blum et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY) (http://creativecommons.org/licenses/by/4.0/) which permits commercial use, including reproduction, adaptation, and distribution of the article provided the original author and source are credited.

Published by United Scientific Group
© United Scientific Group, 2088 B2 Walsh Avenue, Santa Clara, CA 95050, USA | Terms and Conditions | Privacy Policy