Synaptamine (SG8839), An Amino-Acid Enkephalinase Inhibition Nutraceutical Improves Recovery of Alcoholics, A Subtype of Reward Deficiency Syndrome (RDS)
Thomas J.H. Chen,
Seth H. Blum,
Manuel Martinez Pons,
Julie F. Mengucci,
Roger L. Waite,
Eric R. Braverman
The present research was conducted to test the hypothesis that manipulation of the reward neural circuitry by utilization of oral and intravenous amino-acidenkephalinase therapy would improve both the emotional and behavioral symptomology of recovering 600 alcoholics in an open trial clinical study. Our findings suggest that the combination of both oral and intravenous administration of SG8839 significantly improved both the emotional and behavioral recovery of the alcoholic subjects when compared to pre and post administration scores, including reduction of craving (p<0.001), reduced depression (p<0.001), reduced anxiety (p<0.001), anger (p<0.001), fatigue (p<0.001), lack of energy (p<0.001) and crisis (p<0.001). Mean reductions for anxiety (53.8±10.2%), craving (76.3±3.1%), depression (61.0±6.3%), fatigue (76.9±3.1%) and crisis (53.8±5.5%) were all significantly greater than 50% (p<0.001). This is the first study combining both oral and intravenous solutions suggesting clinical improvement.
to cite this article:
Kenneth Blum, Thomas J.H. Chen, B.W. Downs, Brian Meshkin, Seth H. Blum, Manuel Martinez Pons, Julie F. Mengucci, Roger L. Waite, Vanessa Arcuri, Michael Varshofsiky and Eric R. Braverman, 2007. Synaptamine (SG8839), An Amino-Acid Enkephalinase Inhibition Nutraceutical Improves Recovery of Alcoholics, A Subtype of Reward Deficiency Syndrome (RDS). Trends in Applied Sciences Research, 2: 132-138.
Despite approval by the US. FDA of two drugs for the treatment of alcoholism, the narcotic antagonist Naltrexone and the glutamate receptor agonist, Acamprosate®, the rate of recovery following these two drugs has been only moderate.
We believe that these drugs fall short because they only affect either the
opioid receptor or glutamate receptor systems. While it is well established
that addictive behavior, such as alcoholism, is a multi-factorial disease that
has both genetic and environmental antecedents, it would be more prudent to
provide treatment that couple these multiple systems. Previous literature suggested
that alteration of the brain reward cascade (Blum and Kozlowski, 1990) by utilization
of oral precursor amino-acids and enkephalinase inhibition therapy produced
significant reductions in alcohol withdrawal symptomology and alcohol/drug/glucose
craving behavior in a number of controlled studies (Blum et al., 1988a-c,
1990b, 1997; Brown et al., 1990; Defrance et al., 1997; Cold,
1996; Chen et al., 2004).
In 1996, our laboratory first described Reward Deficiency Syndrome (RDS) to define a common genetic variant involving dopamine D2 receptor gene (DRD2) polymorphisms as a putative predictor of impulsive, compulsive and addictive behaviors (Blum et al., 1996a). The D2 receptor has been associated with pleasure and the DRD2 A1 allele has been referred to as the reward gene (Blum et al., 1990a, 1996a; Blum and Braverman, 2000).
The dopamine D2 (DRD2) gene and especially its allele Taq1 A1 and its receptor, also may be involved in co-morbid antisocial personality disorder symptoms (Ponce et al., 2003), high novelty seeking (Noble et al., 1998) and related traits (Hill et al., 1999). The mesocorticolimbic dopaminergic pathway system plays an especially important role in mediating reinforcement by abusable drugs and it may be a common denominator for multiple addictions and a number of psychiatric disorders (Comings et al., 1991).
When the mesocorticolimbic system dopamine reward system dysfunctions (potentially caused by certain genetic variants), the end result is Reward Deficiency Syndrome (RDS) and subsequent drug-seeking behavior (Blum et al., 1996a, b). RDS refers to the breakdown of the reward cascade (Blum and Koslowski, 1990) and resultant aberrant conduct due to specific genetic and environmental influences (Rowe, 1986).
It is well known that alcohol and other drugs of abuse, as well as most positive re-inforcers (i.e., sex, food, gambling, aggression) cause activation and neuronal release of brain dopamine, which can decrease negative feelings and satisfy abnormal cravings (Gessa et al., 1985; Dichiara and Impereto, 1988; Blum, 1991; Noble et al., 1994; Adler et al., 2000). A deficiency or absence of the D2 receptors then predisposes individuals to a high risk for multiple addictive, impulsive and compulsive behaviors (Comings and Blum, 2000). Although other neurotransmitters (e.g., glutamate, gamma-aminobutyric acid (GABA), serotonin and enkephalins) may be important in determining the rewarding and stimulating effects of ethanol, dopamine may be critical for initiating drug use and for reinstating drug use during protracted abstinence (Gardner, 1997; Connor et al., 2002).
A number of studies have observed that the Taq1 A1 allele is associated with low dopamine D2 densities in alcoholics (Noble et al., 1992; Hietala et al., 1994; Tihonen et al., 1995; Little et al., 1998; Repo et al., 1999; Kuilkka et al., 1998). Moreover, other studies have confirmed that the striatal post-synaptic D2-receptor densities are low among alcoholics (Volkow et al., 1996).
In light of these and other findings involving the role of dopaminergic activity and alcoholism (Volkow et al., 1996, 1993, 2000, 2001, 2002; Thanos et al., 2005; Noble, 2003), we decided to test the hypothesis that manipulation of the reward neural circuitry and potential NAC dopamine release by utilization of oral and intravenous amino-acid-enkephalinase therapy would improve both the emotional and behavioral symptomology of recovering alcoholics in an open trial clinical study.
MATERIALS AND METHODS
The study protocol was approved by the PATH Foundation IRB (registration
No. IRB00002334) and Ethics Committee and each participant signed an informed
consent. In an outpatient drug educational program and clinic which was linked
to the judicial system of Denver, Colorado, we evaluated 600 moderate to severe
alcoholics (360 males and 240 females) ranging in age from 17 to 65 years. The
period of evaluation was from April 2000 until June 2005. Each subject had a
history of past treatment and multiple relapse failures. During the intake interview
(one-hour structured), an extensive psychosocial history developed by RDS founder,
Dr. Kenneth Blum, [both written and verbal] was taken for each subject. This
evaluation along with the standardized DSM-1V inventory determined each subjects
level of addiction and explored past treatment modalities that appeared to be
ineffective. Utilizing a Visual Analog Scale (VAS 1-10 cm), as well as self
reporting scores (time of entering the treatment clinic and ten weeks later)
concerning a number of emotional (anxiety, depression and anger) and behavioral
(cravings, fatigue, concentration, energy, crisis) parameters, the intensity
of feelings were evaluated. A number of patients were experiencing typical alcohol
induced withdrawal symptoms at the initiation of the treatment. The collection
of data was accomplished by personnel at a treatment program in Denver, Colorado.
The overall program was directed by Dr. Kenneth Blum and all data was blinded
to all other investigators.
Intravenous Solution and Orals
Each patient was treated with a patented intravenous solution containing
certain neurotransmitter precursor amino-acids (DL-Phenylalanine, L-tyrosine,
L-Tryptophan, L-Glutamine) and enkephalinase inhibitors, chromium and other
trace metals (SG8839-exclusively by Salugen, Inc, San Diego, California), for
ten weekly treatments (Fig. 1). Each patient was also asked
to take SG8839 in an oral form as well. Compliance for the orals was determined
by the receipt of at least three monthly bottles of the product. Substance abuse
counseling was also provided to each subject at least 2 times a week and educational
videos were played during IV infusion. Our educational focus was strategically
designed to assist each patient in understanding the RDS theory and how it has
worked in their personal lives. The patients also attended a drug and alcohol
didactic seminar on a weekly basis.
Paired Students t-tests were performed to identify any statistically
significant differences between the pre- and post-treatment values among the
parameters tested, with p<0.01 considered significant.
The following Intensity of Feeling score means and standard deviations were observed for each parameter tested: anxiety (pre: 6.5±0.84 vs. post: 3.0±0.68) (p<0.001]); craving (pre: 5.7±0.57 vs. post: 1.35±0.16) (p<0.001); depression (pre: 5.0±0.35 vs. post: 1.95±0.31) (p<0.001]); fatigue (pre: 5.2±0.57 vs. post: 1.2±0.14) (p<0.001); concentration (pre: 4.9±0.98 vs. post: 4.18±0.54) (p<0.001); anger (pre: 4.24 vs. post: 1.9± 0.36) (p<0.001]; lack of energy (pre: 5.85±0.64 vs. post 3.5±0.47) (p<0.001); and crisis (pre: 6.5±0.65 vs. post: 3.0±0.30) (p<0.001). Further statistical testing using one-sample Students t-tests was done to determine if the average reduction in mean scores due to treatment exceeded 50%, suggesting clinical improvement. Mean reductions for anxiety (53.8±10.2%), craving (76.3±3.1%), depression (61.0±6.3%), fatigue (76.9±3.1%) and crisis (53.8±5.5%) were all significantly greater than 50% (p<0.001). It is noteworthy that, in the 600 alcoholics tested, the only parameters that did not result in clinical improvement after treatment were concentration (14.7±20.2%) and lack of energy (40.2±8.4%) (Fig. 1).
While we are not able to emphatically prove that the improvement in both emotional
and behavioral parameters found in this clinical trial are solely due to the
oral and intravenous amino-acid-enkephalinase therapy (cannot eliminate the
positive affect of drug abuse counseling), these results strongly suggest the
potential significant effects of this novel therapeutic modality.
||Pre- and post intensity of feeling score means of each parameter
tested. For each parameter, the bar represents the pre-test mean and the
right bar displays the post-test mean. The wisker above each bar represents
the standard error of the mean
The notion that the oral and intravenous amino-acid therapy actually paves the way for the patient to intellectually accept RDS as a lifelong condition she/he must face seems to be the key to successful substance abuse treatment. This dual therapeutic approach allows the brain to say No to substance abuse and provides the body with a softer, gentler way. Thus it has become apparent that positive mind-body interaction actually creates the feeling of well-being necessary for successful recovery.
We further hypothesize that SG8839, increases dopamine release at the NAC, thereby activating D2 receptors and reduces alcohol craving behavior (Thanos et al., 2001).
Based on this well-studied foundation, whereby the deficiency or absence of DRD2 receptors then leads to a high risk for multiple addictive, impulsive and compulsive behavioral propensities called Reward Deficiency Syndrome (Blum et al., 1996a, b; Gardner, 1997; Xu et al., 2004), we propose that SG8839, because of its potential induction of a slow, natural, neuronal release of dopamine may indeed be an important treatment modality. This premise warrants further investigation including a double-blinded, randomized, placebo controlled study for both the intravenous and oral forms of delivery of this novel modality.
While there are no controls in this open label study, the strength of the experiment resides in the large sample size (n = 600) and the high levels of significant differences between pre and post measurements.
We further hypothesize that coupling certain gene polymorphisms involved in dopaminergic, serotonergic, gabaergic and catecholamine catabolism enzymes (e.g., Catechol-O-Methyl-Transferase COMT) function to guide customized formulations based on solid nutrigenomic principles may indeed enhance treatment outcomes in the future (Blum et al., 2006).
The authors appreciate the financial support of Salugen, Inc., San Diego, California and Path Research Foundation, New York, New York and in particular Rein Narma. The authors acknowledge the editorial assistance of Gina S. Bender, Edward N. Bender and Randolph Smart.
Blum, K. and E.R. Braverman, 2000. Reward deficiency syndrome a biogenetic model for the diagnosis and treatment of impulsive addictive and compulsive behaviors. J. Psychoact. Drugs, 32: 1-112.
Blum, K. and G.P. Kozlowski, 1990. Ethanol and Neuromodulator Interactions a Cascade Model of Reward. In: Alcohol and Behavior, Ollat, H., S. Parvez and H. Parvez (Eds.). VSP Press, Utrecht, Netherlands. pp: 131-149.
Blum, K. and J. Payne, 1991. Alcohol and the Addictive Brain. 1st Edn., The Free Press, New York, ISBN-10: 0029037018.
Blum, K., B. Meshkin and B.W. Downs, 2006. DNA based customized 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: 1008-1018.
Blum, K., D. Allison, M.C. Trachtenberg and Others, 1988. Reduction of both drug hunger and withdrawal against advise rate of cocaine abusers in a 30 day inpatient treatment program by the neuronutrient tropamine. Curr. Therap. Res., 43: 1204-1214.
Blum, K., E.P. Noble, P.J. Sheridan, A. Montgomery and T. Ritchie et al., 1990. Allelic association of human dopamine D2 receptor gene in alcoholism. J. Am. Med. Assoc., 263: 2055-2060.
Blum, K., E.R. Braverman, R.C. Wood, J. Gill and C. Li et al., 1996. Increased prevalence of the taq1 a1 allele of the dopamine receptor gene in obesity with comorbid substance use disorder. Pharmacogenetics, 6: 297-305.
Blum, K., J.G. Cull, E.R. Braverman and D.E. Comings, 1996. Reward deficiency syndrome. Am. Scientist, 84: 132-145.
Blum, K., J.G. Cull, J.H.T. Chen, S.G. Swan and J.M. Holder et al, 1997. Clinical evidence for effectiveness of phencal TM in maintaining weight loss in an open label controlled 2 year study. Curr. Therap. Res., 58: 745-763.
Blum, K., M.C. Trachtenberg and D.W. Cook, 1990. Neuronutrient effects on weight loss in carbohydrate bingers an open clinical trial. Curr. Therap. Res., 48: 217-233.
Direct Link |
Blum, K., M.C. Trachtenberg and J. Ramsey, 1988. Improvement of inpatient treatment of the alcoholic as a function of neurotrient restoration. A pilot study. Intl. J. Addiction, 23: 991-998.
Blum, K., M.C. Trachtenberg, C.E. Elliott, M.L. Dingler, R.L. Sexton, A.I. Samuels and L. Cataldie, 1988. Enkephalinase inhibition and precursor amino acid loading improves inpatient treatment of alcohol and polydrug abusers doubleblind placebo controlled study of the nutritional adjunct SAAVE. Alcohol, 5: 481-493.
Brown, R.J., K. Blum and M.C. Trachtenberg, 1990. Neurodynamics of relapse prevention a neuronutrient approach to outpatient DUI offenders. J. Psychoactive Drugs, 22: 173-187.
Chen, T.J.H., K. Blum, J.T. Payte, J. Schoolfield, D. Hopper, M. Stanford and E.R. Braverman, 2004. Narcotic antagonists in drug dependence pilot study showing enhancement of compliance with STN 10 amino acid precursors and enkephalinase inhibition therapy. Med. Hypothesis, 63: 538-548.
Cold, J.A., 1996. Neurecover sa in the treatment of cocaine withdrawal and craving a pilot study. Clin. Drug Investigations, 12: 1-7.
Comings, D.E. and K. Blum, 2000. Reward deficiency syndrome genetic aspects of behavioral disorders. Progress Brain Res., 126: 325-341.
Comings, D.E., B.G. Comings, D. Muhleman, G. Dietz and B. Shahbahrami et al., 1991. The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. J. Am. Med. Assoc., 266: 1793-1800.
Connor, J.P., R.M. Young, B.R. Lawford, T.L. Ritchie and E.P. Noble, 2002. D2 dopamine receptor (DRD2) polymorphism is associated with severity of alcohol dependence. Eur. Psychiatry, 17: 17-23.
Defrance, J.J., C. Hymel and M.C. Trachtenberg et al., 1997. Enhancement of attention processing by kantrol in healthy humans. A pilot study. Clin. Electroencephal., 28: 68-75.
Di Chiara, G. and A. Impereto, 1988. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic systems of freely moving rats. Proc. National Acad. Sci. USA., 85: 5274-5278.
Direct Link |
Gardner, E.L., 1997. Brain Reward Mechanisms. In: Substance Abuse: A Comprehensive Textbook, J.H., P. Ruiz, R.B. Millman and J.G. Langrod (Eds.). 3rd Edn., Williams and Wilkins, Baltimore, pp: 51-58.
Gessa, G.L., F. Mutoni, M. Coller, L. Vargin and G. Mercer, 1985. Low doses of ethanol activate dopaminergic neurons in the ventral tegmental area. Brain Res., 348: 201-203.
Hietata, J., C. West, E. Syvalahti, K. Nagren, P. Lehikoinen and U. Sonninen, 1994. Striatal D2 dopamine receptor binding characteristics in vivo in patients with alcohol dependence. Psychopharmacology, 116: 285-290.
Hill, S.Y., N. Zezza, G. Wipprecht, J. Locke and K. Neiswanger, 1999. Personality traits and dopamine receptors (D2 and D4) linkage studies of alcoholics. Am. J. Med. Genet., 88: 634-641.
CrossRef | PubMed | 3.0.CO;2-M target='_blank' class='botlinks'>Direct Link |
Kuilkka, J.T., J.L. Baulieu, J. Hiltunen and C. Halldin et al., 1998. Pharmacokinetics and dosimetry of iodine 123 labeled Pe21 in humans a radioligand for dopamine transporter imaging. Eur. J. Nucl. Med., 25: 531-534.
PubMed | Direct Link |
Little, K.Y. and L. Zang, 1999. Striatal dopaminergic abnormalities in human cocaine users. Am. J. Psychiat., 156: 238-245.
PubMed | Direct Link |
Noble, E.P., 2003. D2 Dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. Am. J. Med. Genet., 116: 103-125.
CrossRef | PubMed | Direct Link |
Noble, E.P., K. Blum, T. Ritchie, A. Montgomery and P. Sheridan, 1992. Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics. Arch. Gen. Psychiat., 48: 648-654.
PubMed | Direct Link |
Noble, E.P., K. Syndilko, R.J. Fitch, T. Ritchie and M.C. Bohlman et al., 1994. D2 dopamine receptor taq1 A alleles in medically ill alcoholic and nonalcoholic patients. Alcohol , 29: 729-744.
Noble, E.P., T.Z. Ozkaragoz, T. Ritchie, X. Zhang, T.R. Bekin and R.S. Sparkes, 1998. D2 and D4 dopamine receptor polymorphisms and personality. Am. J. Med. Gene., 81: 257-267.
CrossRef | PubMed | 3.0.CO;2-E target='_blank' class='botlinks'>Direct Link |
Repo, E., J.T. Kuikka, K.A. Bergstrom, J. Karhu, J. Hiltunen and J. Tiihonen, 1999. Dopamine transporter and D2 receptor density in late-onset alcoholism. Psychopharmacology, 147: 314-318.
CrossRef | PubMed | Direct Link |
Rowe, D.C., 1986. Genetic and environmental components of antisocial behavior a study of 265 twin pairs. Criminology, 24: 513-532.
CrossRef | Direct Link |
Thanos, P.K., N.D. Volkow and P. Freimith et al., 2001. Overexpression of dopamine D2 receptors reduces alcohol self administration. J. Neurochemist., 78: 1094-1103.
CrossRef | PubMed | Direct Link |
Thanos, P.K., S.N. Rivera, K. Weaver, D.K. Grandy and M. Ruberstein et al., 2005. Dopamine D2R transfer in dopamine d2 receptor deficient mice effects on ethanol drinking. Life Sci., 77: 130-139.
CrossRef | PubMed | Direct Link |
Tihonen, J., J. Kuikka, K. Bergstrom, P. Hakola, J. Karhu, O.P. Ryynanen and J. Fohr, 1995. Altered striatal dopamine re uptake site densities in habitually violent and non violent alcoholics. Nature Med., 1: 654-657.
Volkow, N.D. and J.S. Fowler, 2000. Addiction, a disease of compulsion and drive Involvement of the orbitofrontal cortex. Cerebral Cortex, 10: 318-325.
Direct Link |
Volkow, N.D., G.J. Wang, J.S. Fowler, R. Chen and N.O. Volkow et al., 1996. Decreases in dopamine receptors but not in dopamine transporters in alcoholics. Alcohol Clin. Exp. Res., 20: 1594-1598.
Volkow, N.D., J.S. Fowler and G.J. Wang, 2002. Role of dopamine in drug reinforcement and addiction in humans results from imaging studies. Behavioral Pharmacol., 13: 355-366.
Volkow, N.D., J.S. Fowler and G.J. Wang, 2003. The addicted human brain insights from imaging studies. J. Clin. Investigat., 111: 1444-1451.
Volkow, N.D., J.S. Fowler, G.J. Wang, R. Hitzman and J. Logan et al., 1993. Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse, 14: 169-177.
Volkow, N.D., L. Chang, G.J. Wang, J.S. Fowler and Y.S. Ding et al., 2001. Low level of brain dopamine D2 receptors in methamphetamine abusers association with metabolism in the orbitofrontal cortex. Am. J. Psychiatry, 158: 377-382.
Xu, K., D. Lichterman, R.H. Kipsky, P. Franke and X. Liu et al., 2004. Association of specific haplotypes of D2 dopamine receptor gene with vulnerability to heroin dependence in distinct populations. Arch. Gen. Psychiatry, 61: 567-606.