[18] Blum K, Calhoun W, Merritt J, Wallace JE (1973) L-DOPA: effect on ethanol narcosis and brain biogenic amines in mice. Nature 242: 407-409. •Increased brain L-DOPA increases brain dopamine in mice and causes alcohol induced inebriated mice to sleep longer.
•Dopamine, 1-tryptophan and alcohol work similarly in the brain.
[19] Blum K, Wallace JE, Calhoun W, Tabor RG, Eubanks JD (1974) Ethanol narcosis in mice: serotonergic involvement. Experientia 30:1053-1054. •When mice were given alcohol and 1-tryptophan compared to saline the L-tryptophan plus alcohol group slept longer than saline plus alcohol group.
•1-tryptophan and alcohol work similarly in the brain.
[28] Blum K, Allison D, Trachtenberg MC, Williams RW, Loeblich LA (1988) Reduction of both drug hunger and withdrawal against advice rate of cocaine abusers in a 30 day inpatient treatment program by the neuronutrient Tropamine. Current Therapeutic Research 43: 1204-1214. •Comparison of the effects of Tropamine [T] – (amino acid and vitamin supplement), SAAVE [S]-(a neuronutrient supplement) and no supplement [C] on a group of cocaine abusers in a 30 day hospital treatment program.
•AMA rate: - [C] 37.5%
- [S] 26.6%
- [T] 4.2 %•Tropamine decreased the AMA rate by significant reduction of drug hunger.
[48] Blum K, Stice E, Liu Y, Giordano J, Morse S, et al. (2011) “Dopamine Resistance” in brain reward circuitry as a function of DRD2 gene receptor polymorphisms in RDS: Synaptamine complex variant (KB220) induced “Dopamine Sensitivity” and enhancement of happiness. XIX World Congress of Psychiatric Genetics, September 10-14th, Washington DC. •In a cross over triple –blind –placebo controlled study on ten Chinese abstinent (16 months) heroin dependent patients, fMRI was utilized to assess dopaminergic BOLD activation in the brain.
•KB220Z was administered to each patient and after one hour it was found that the complex induced BOLD activation of caudate-accumbens dopaminergic activation.
•The BOLD activation was significantly different compared to placebo.
•In addition KB220Z also reduced the hyper-excitability of putamen.
•The authors suggest that KB220Z induces “dopamine sensitivity” in genetically prone “dopamine resistant “patients genotyped for various reward gene polymorphisms.
[52] Blum K, Briggs AH, Trachtenberg MC, Delallo L, Wallace JE, (1987) Enkephalinase inhibition: regulation of ethanol intake in genetically predisposed mice. Alcohol 4: 449-456. •Mice genetically predisposed to like alcohol have a measured deficiency in enkephalin.
•D-phenylalanine and hydrocinnamic acid are substances known to stop the breakdown of enkephalin in the brain -the amount of enkephalin available in the brain increases.
•When the amount of enkephalin available in the brain increases both voluntary and forced intake of alcohol decreases.
D-phenylalanine is one of the ingredients in NAAT.
[56] Miller DK, Bowirrat A, Manka M, Miller M, Stokes S, et al. (2010) Acute intravenous synaptamine complex variant KB220™ "normalizes" neurological dysregulation in patients during protracted abstinence from alcohol and opiates as observed using quantitative lectroencephalographic and genetic analysis for reward polymorphisms: part 1, pilot study with 2 case reports. Postgrad Med 122: 188-213. •Combination of both IV –NAAT and oral forms
•Two case reports of an alcoholic and heroin addict
•Both patients were genotyped for a number of neurotransmitter reward genes to determine to what extent they carry putative dopaminergic risk alleles that may predispose them for alcohol or heroin dependence, respectively.
•The genes tested included the dopamine transporter (DAT1, locus symbol SLC6A3), dopamine D4 receptor exon 3 VNTR (DRD4), DRD2 TaqIA (rs1800497), COMT val158 met SNP (rs4680), monoamine oxidase A upstream VNTR (MAOA-uVNTR), and serotonin transporter-linked polymorphic region (5HTTLPR, locus symbol SLC6A4).
•Both patients showed prevalence of at least one risk allele.
•qEEG analysis revealed dys-regulation in the PFC-Cingulate Gyrus in both addicts.
•IV-NAAT and oral produced a regulation of widespread theta activity
•These results have relevance for relapse prevention because of its effect on the part of brain involved in relapse (PFC-Cingulate Gyrus).
[57] Blum K, Chen TJ, Morse S, Giordano J, Chen AL, et al. (2010) Overcoming qEEG abnormalities and reward gene deficits during protracted abstinence in male psychostimulant and polydrug abusers utilizing putative dopamine D2 agonist therapy: part 2. Postgrad Med 122: 214-226. •In a cross over study a total of 10 abstinent Psychostimulant dependent patients were randomized in a triple –blind –placebo controlled study.
•Each patient was genotyped for a number of reward genes for addiction risk assessment.
•100% of the patient carried a least on risk allele.
•qEEG analysis was performed on each patient one-hour after administration of KB220Z powder.
•KB220Z™ showed an increase of alpha waves and low beta wave activity in the parietal brain region (relapse area).
•Authors propose that utilization of KB220Z may up-regulate dopamine receptors in patients having moderate to high genetic addiction risk.
[61] Blum K, Trachtenberg MC, Elliott CE, Dingler ML, Sexton RL (1988) 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. Alcohol 5: 481-493. •Double blind placebo controlled clinical trial of SAAVE of 62 people with Substance Use Disorder (SUD).
- reduced stress as measured by skin conductance,
- improved Physical and BESS (behavioral, emotional, social and spiritual) Scores,
- Six-fold decrease in leaving Against Medical Advice (AMA) rates.
[62] Blum K, Chen ALC, Chen TJH, Bowirrat A, Waite RL, et al. (2009) Putative targeting of Dopamine D2 receptor function in Reward Deficiency Syndrome (RDS) by Synaptamine Complex™ Variant (KB220): Clinical trial showing anti-anxiety effects. Gene Ther Mol Biol 13: 214-230. •Double-blind-placebo controlled study to determine anti-anxiety effects of KB220 (Synaptamine Variant) in 62 alcoholic and poly-drug abusers
•This was an objective test not subjective because antianxiety effect evaluated by skin conductance level (SCL).
•Significant reduction of stress in the KB220 group compared to placebo including a Time by-treatment interaction. Positive anti-anxiety effect as monitored throughout a 28 day treatment period is most significant at the 7th day ( a time with the most severe anxiety).
•These findings may be relevant to prevention of relapse.
[63] Blum K, Trachtenberg MC, Ramsay JC (1988) Improvement of inpatient treatment of the alcoholic as a function of neurotransmitter restoration: a pilot study. The International Journal of the Addictions 23: 991-998. •First small clinical trial of SAAVE (precursor amino acid loading and enkephalinase inhibition -earliest version of NAAT).
•Designed to elevate levels of enkephalin(s), serotonin, catecholamines, and regulate GABA, thought to be deficient in alcoholics.
•Compared to controls those who took SAAVE had:
- lower building up to drink score,
- required no PRN benzodiazepines,
- ceased having tremors 24 hrs earlier
- had less depression.
[65] Brown RJ, Blum K, Trachtenberg MC (1990) Neurodynamics of relapse prevention: a neuronutrient approach to outpatient DUI offenders Journal of Psychoactive Drugs 22: 173-187. •Relapse prevention using neuronutrients SAAVE and Tropamine in DUI offenders; either alcohol or cocaine.
•Reduced relapse rates and enhanced recovery in 10 week outpatient setting.
•After 10 months recovery rate was SAAVE 73% and Tropamine 53%.
•These recovery rates are significantly better than the literature average for both alcoholism and cocaine dependence.
[70] DeFrance JF, Hymel C, Trachtenberg MC, Ginsberg LD, Schweitzer FC et al. (1997) Enhancement of attention processing by Kantroll in healthy humans: a pilot study. Clinical Electroencephalography 28: 68-75. •Cognitive processing speeds in normal young adult volunteers were measured before and after 28-30 days of supplementation with a combination of amino acids-enkephalinase inhibition (NAAT), vitamins and minerals.
•Cognitive processing speeds were enhanced by statistically significant amplitude of the P300 component of the Event Related Potentials (ERPs). FOCUS IMPROVED
•These findings have relevance to relapse prevention because the resultant enhanced effect following NAAT as measured by the Contingent Continuous Performance Task (CCPT); Spatial Orientation Task (SOT) and focus reflects better judgment and thus decision making.
[75] Blum K, Chen TJH, Downs BW, Meshkin B, Blum SH, et al. (2007) Synaptamine (SG8839), TM An Amino-Acid Enkephalinase Inhibition Nutraceutical Improves Recovery of Alcoholics, A Subtype of Reward Deficiency Syndrome (RDS). Trends in Applied Sciences Research 2 (3): 132-138. •In an open clinical study Intravenous plus oral Amino-Acid Enkephalinase Inhibition Nutraceutical improved symptomatology of 600 recovering Alcoholics.
•Emotional and behavioral recovery scores significantly improved after administration of oral and intravenous Synaptamine.
•Mean reductions for craving, depression, anxiety, anger, fatigue, lack of energy and crisis were all significantly greater than 50% (p<0.001).
[92] Blum K, Chen TJH, Chen ALC, Rhodes P, Prihoda TJ, et al. (2008) Dopamine D2 Receptor Taq A1 allele predicts treatment compliance of LG839 in a subset analysis of pilot study in the Netherlands. Gene Ther Mol Biol 12: 129-140. •This study evaluated the importance of carrying the dopamine D2 receptor A1 allele and treatment compliance of n in an Obese Dutch population nutraceutical intervention to combat obesity.
•Candidate genes to be associated with obesity include amongst others the dopamine D2 receptor (DRD2), methylenetetrahydrofolate reductase (MTHFR), serotonin receptor (5-HT2a), Peroxisome Proliferator Activated Receptor gamma (PPAR-γ), and Leptin (OB) genes.
•Compliance 2 fold better in carriers of DRD2 A1 allele compared to DRD2 A2 allele.
•Suggests if you need to enhance dopamine compliance is better.
[97] Chen TJH , Blum K, Kaats G, Braverman ER, Eisenberg A, et al. (2007) Chromium Picolinate (Crp) A putative Anti-Obesity Nutrient Induces Changes In Body Composition As Function Of The Taq1 Dopamine D2 Receptor polymorphisms in a randomized double-blind placebo controlled study. Gene Therapy and Molecular Biology 11: 161-170. •Chromium Picolinate (CrP) was tested against placebo in groups of obese patients tested for the Taq1 Dopamine D2 Receptor Gene.
•In carriers of the DRD2 A2 genotype weight loss and other changes in body composition were significant.
•They were not significant for patients with the A1/A1 or A1/A2 allele.
•These results suggest that the dopaminergic system, specifically the density of the D2 receptors, confers a significant differential therapeutic effect of CrP in terms of weight loss and change in body fat.
•It is speculated that carriers of the DRD2 A1 allele had aberrant sugar cravings which masked the effects of CRP.
[103] Chen TJ, Blum K, Waite RL, Meshkin B, Schoolfield J, et al. (2007) Gene Narcotic Attenuation Program attenuates substance use disorder, a clinical subtype of reward deficiency syndrome. Advances in Therapy 24: 402-414. •1-year prospective study that evaluated the effects of taking Haveos (SynaptamineTM) on 61 compliant patients in a comprehensive outpatient clinical program.
•Results after 12 weeks:
•Results after 1 year:
•Building up to relapse scores and ability to refrain from drug-seeking behavior both significantly improved.
•Dropout rate: Alcohol users 7% and Psychostimulant users 73%
[105] Chen D, Liu Y, He W, Wang H, Wang Z (2012) Neurotransmitter-precursor-supplement Intervention for Detoxified Heroin Addicts. Med Sci 32: 422-427. •In the cluster-randomized placebo-controlled trial, 83 detoxified heroin addicts were evaluated during withdrawal.
•This study examined the effects of combined administration of tyrosine, lecithin, L-glutamine and L-5-hydroxytryptophan (5-HTP) on heroin withdrawal syndromes and mental symptoms.
•The experimental group compared to placebo had reduced insomnia, and reduced withdrawal scores.
•After 6 days of treatment compared to placebo the experimental group had a d significant reduction in tension-anxiety, depression-dejection, anger-hostility, fatigue-inertia and total mood disturbance, and a greater increase in their vigor-activity symptoms (all P<0.05).
[115] Blum K, Trachtenberg MC, Cook DW (1990) Neuronutrient effects on weight loss in carbohydrate bingers; an open clinical trial. Curr Ther Res 48: 217-233. •Examine the effects of PCAL-103 (NAAT) on compulsive eating and weight loss in 27 outpatients attending a supervised diet-controlled treatment program.
•The PCAL-103 average weight loss was 26.96 lbs vs 10.2 lbs in the control group. Relapse 18.2% in the PCAL-103 group vs 81.8% in the control group.
[116] Cold, Julie A (1996) NeuRecover-SATM in the Treatment of Cocaine Withdrawal and Craving: A Pilot Study. Clinical Drug Investigation 12: 1-7. •Small preliminary double-blind, placebo-controlled study of efficacy of NeuRecover-SATM (formerly Tropamine+TM) in the treatment of cocaine withdrawal and craving.
•Cocaine craving decreased significantly in the NeuRecover-SATM group compared to placebo.
[117] Blum K, Cull JG, Chen TJH, Swan SG, Holder JM, et al. (1997) Clinical evidence for effectiveness of Phencal™ in maintaining weight loss in an open-label, controlled, 2-year study. Current Therapeutic Research 58: 745-763. •Of 247 Outpatients in a very-low-calorie fasting program 130 who were having difficulty attaining their desired weight or maintaining their desired weight constituted the experimental group who took PhenCal™ plus Centrum Vitamins and the rest 117 took only vitamins (Centrum) 117 were the control group.
•The PhenCal™ group compared to the control:
•- lost twice as much weight,
•- regained 14.7% of the weight while the control group regained 41.7%,
•- decrease in food cravings (sugar) for females 70% and males 63%,
•- decrease in binge eating for females 66% and males 41%.
[118] 1st Conference on Reward Deficiency Syndrome: Genetic Antecedents and Clinical Pathways. San Francisco, California, USA. November 12-13, 2000. Abstracts. Amino-acid precursor and enkephalinase inhibition therapy: evidence for effectiveness in treatment of “Reward Deficiency Syndrome (RDS) with particular emphasis on eating disorders.
Julia Ross.
Mol Psychiatry. Feb; 6(1 Suppl 1):S1-8, 2001.
•Preliminary evaluation of six randomly selected former eating disordered female clients (three were also chemically dependent), contacted at 9 months and 3 years of treatment with amino-acid precursor and enkephalinase inhibition therapy.
•All 6 reported initial benefit, one relapsed at 6 months the other 5 all sustained, and in some cases exceeded expectations.
•98% of 100 patients similarly treated and evaluated reported significant improvement in both mood and reduced substance craving.
[119] Chen TJ, Blum K, Payte JT, Schoolfield J, Hopper D, et al. (2004) Narcotic antagonists in drug dependence: pilot study showing enhancement of compliance with SYN-10, amino-acid precursors and enkephalinase inhibition therapy. Medical Hypotheses 63: 538-548. •A combination of Trexan (a narcotic antagonist) and amino-acids was use to detoxify either methadone or heroin addicts.
•Results were dramatic in terms of significantly enhancing compliance to continue taking Trexan:
•-Trexan alone for rapid detoxification the average number of days of compliance calculated on 1000 patients is 37 days.
•-12 subjects tested, receiving both the Trexan and amino-acid therapy continued to take the combination for an average of 262 days.
•Suggests:- coupling amino-acid therapy and enkephalinase inhibition, while blocking the delta-receptors with a pure narcotic antagonist as a novel method to induce rapid detox in chronic methadone patients and prevent relapse;
•- testing this hypothesis with the sublingual combination of the partial opiate mu receptor agonist buprenorphine.
[120] Blum K, Chen TJ, Meshkin B, Downs BW, Gordon CA, et al. (2006) Reward deficiency syndrome in obesity: a preliminary cross-sectional trial with a Genotrim variant. Adv Ther 23: 1040-1051. •Consumption of large quantities of alcohol or carbohydrates (carbohydrate bingeing) stimulates production and usage of dopamine within the brain.
•Obesity is due to the need to make up for inadequate dopaminergic activity in the reward center of the brain.
•This has been called reward deficiency syndrome (RDS) used to categorize such genetic biologic influences on behavior.
•RDS must be addressed at the same time as behavioral modifications are implemented to adequately treat obese patients.
•In this small observational trial; 24 individuals completed a survey on which they documented 15 categories of benefit during their experience with a GenoTrim a NAAT formulation customized to DNA.
•Statistical analysis of the survey results demonstrated that stress reduction lead to:
•-(1) improved sleep, enhanced energy, and improved focus and performance;
•- (2) reduced appetite, loss of unwanted weight, decreased body inches, and enhanced well-being.
[121] Blum K, Chen TJH, Williams L, Chen ALC, Downs WB, et al. (2008) A short term pilot open label study to evaluate efficacy and safety of LG839, a customized DNA directed nutraceutical in obesity: Exploring Nutrigenomics. Gene Ther Mol Biol 12: 371-382. •Preliminary investigational study to evaluate the impact of polymorphisms of five candidate genes on treatment for obesity with NAAT.
•The formula for each patient was customized based on their genetic results.
•Pre- NAAT compared to Post-NAAT had significantly lower BMI.
•Pre- NAAT compared to Post-NAAT had significantly lower pounds.
•Pre- NAAT compared to Post-NAAT had trends for reduced late night snacking, carbohydrate craving reduction, reduction of stress, reduction of waist circumference.
[122] Blum K, Chen AL, Chen TJ, Rhoades P, Prihoda TJ, et al. (2008) LG839: anti-obesity effects and polymorphic gene correlates of reward deficiency syndrome. Adv Ther 25: 894-913. •First DNA Customized analysis of LG839 for weight management effects.
•Out of 1058 Dutch participants a subset of 27 self –reported obese subjects were genotyped and based on their polymorphisms each subject utilized a customized LG839 variant assessed for pre –and post for after 80 days of usage.
•Significant results were observed for weight loss, sugar craving reduction, appetite suppression, snack reduction, reduction of late night eating (all P<0.01), increased perception of overeating, enhanced quality of sleep, increased happiness (all P<0.05), and increased energy (P<0.001).
•The study points to the importance of genotyping patients and providing DNA customized nutraceutical intervention to combat obesity.
[123] Braverman ER, Braverman D, Acrui V, Kerner M, Downs BW, Blum K (2010) Sustainable Weight Loss and Muscle Gain Utilizing the Rainbow Diet™: Targeting Noradrenergic and dopaminergic Mechanistic Sites, Hormonal Deficiency Repletion Therapy and Exercise: A case report. The American Journal of Bariatric Medicine 25: 18-28. •Case study of 58 Y old male identified as being obese utilized a special Rainbow Diet.
•Patient received Noradrenergic drug; NAAT (a natural D2 agonist); hormonal deficiency replacement therapy and light exercise.
•After one year BMI decreased; Percent body fat decreased; improved cardiac function; fasting glucose level declined; Prostate Specific Antigen (PSA) tripled; memory improved; testosterone levels increased.
•There was sustainable weight loss and muscle gain.
[124] Merlene Miller, Amanda LC Chen, Stan D. Stokes, Susan Silverman, Abdalla Bowirrat, et al. Early Intervention of Intravenous KB220IV- Neuroadaptagen Amino-Acid Therapy (NAAT)™ Improves Behavioral Outcomes in a Residential Addiction Treatment Program: A Pilot Study. Journal of Psychoactive. •In 129 patients a combination of IV and oral NAAT therapy (generic KB220) were assessed for Chronic Abstinence Symptom Severity (CASS) Scale over a 30 day period.
•Three scales were constructed based on this factor analysis: Emotion, Somatic, and Cognitive.
•All three scales showed significant declines (p=.00001) from pre- to post-treatment: t=19.1 for Emotion, t=16.1 for Somatic, and t=14.9 for poor - Cognitive.
•A two year follow-up in a subset of 23 patients showed: 21 (91%) were sober at 6 months 19 (82%) having no relapse; 19 (82%) were sober at one year with 18 (78%) having no relapse; 21 (91%) were sober at two years post-treatment with 16 (70%) having no relapse.
Table 2: Phase 1 and Phase 2 Clinical Trials of Neuro-nutrient Amino Acid Therapy (NAAT)
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