Table 2: Clinical benefits of KB220Z.

Pre-clinical
Year	Reference	Key points
1973	Blum K, et al. [53]	Increased brain L-DOPA increases brain dopamine in mice and causes inebriated mice to sleep. Dopamine, 1-tryptophan, and alcohol work similarly in the brain.
1974	Blum K, et al. [54]	When mice were given alcohol and 1-tryptophan or saline, the mice given 1-tryptophan went to sleep. The mice given saline did not. 1-tryptophan and alcohol work similarly in the brain.
1987	Blum K, et al. [55]	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.
Clinical
Year	Reference	Key points
1988	Blum K, et al. [22]	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 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 hours earlier, and had less depression.
	Blum K, et al. [56]	Double-blind placebo-controlled clinical trial of SAAVE of 62 people with Substance Use Disorder (SUD). Results reduced stress as measured by skin conductance, improved Physical and BESS (behavioral, emotional, social and spiritual) Scores, and had a six-fold decrease in leaving Against Medical Advice (AMA) rates.
	Blum K, et al. [57]	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%, and [T] 4.2%. Tropamine decreased the AMA rate by significant reduction of drug hunger.
1990	Brown RJ, et al. [25]	Relapse prevention using neuro nutrients 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%.
	Blum K, et al. [58]	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.
1996	Cold JA, et al. [59]	Small preliminary study of efficacy of NeuRecover-SATM (formerly Tropamine + TM) in the treatment of cocaine withdrawal and craving. Cocaine craving decreased significantly in the Neu Recover-SATM group.
1997	DeFrance JF, et al. [60]	Cognitive processing speeds in normal young adult volunteers were measured before and after 28-30 days of supplementation with a combination of amino acids (NAAT), vitamins, and minerals. Cognitive processing speeds were enhanced by a statistically significant amplitude of the P300 component of the Event Related Potentials (ERPs). Focus improved.
	Blum K, et al. [61]	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™ and of the rest, 117 took vitamins and 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 for females 70% and males 63%, and decreased in binge eating for females 66% and males 41%.
2001	Ross J, et al. [62]	Preliminary evaluation of six randomly selected former eating disorder 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.
2004	Chen TJ, et al. [63]	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, taking 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, and testing this hypothesis with the sublingual combination of the partial opiate mu receptor agonist buprenorphine.
2006	Blum K, et al. [64]	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 improved sleep, enhanced energy, and improved focus and performance, reduced appetite, loss of unwanted weight, decreased body inches, and enhanced well-being.
2007	Chen TJ, et al. [65]	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 include significant decrease in craving. Results after 1 year include building up to relapse scores and ability to refrain from drug-seeking behavior both significantly improved. The dropout rate for alcohol users 7% and psychostimulant users 73%.
	Blum K, et al. [66]	In an open clinical study, 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).
	Chen TJH, et al. [67]	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.
	Blum K, et al. [68]	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.
2008	Blum K, et al. [69]	A novel experimental DNA-customized nutraceutical, LG839. Polymorphic correlates were obtained for a number of genes (LEP, PPAR-gamma2, MTHFR, 5-HT2A, and DRD2 genes) with positive clinical parameters tested in this study. Significant results were observed for weight loss, sugar craving reduction, appetite suppression, snack reduction, reduction of late night eating, increased energy, etc. Only the DRD2 gene polymorphism (A1 allele) had a significant Pearson correlation with days on treatment.
	Blum K, et al. [21]	Hypothesized that genotyping certain known candidate genes would provide DNA-individualized customized nutraceuticals that may have significant influence on body re-composition by countering various genetic traits. Genotyped for the dopamine D2 receptor (DRD2), methylenetetrahydrofolate reductase (MTHFR), serotonin receptor (5-HT2a), Peroxisome Proliferator Activated Receptor gamma (PPAR-γ), and Leptin (OB) genes. Systematically evaluated the impact of polymorphisms of these five candidate genes as important targets for the development of a DNA-customized nutraceutical LG839 [dl-phenylalanine, chromium, l-tyrosine other select amino-acids and adaptogens] to combat obesity with special emphasis on body recomposition as measured by Body Mass Index (BMI). In the 41-day period, we found a trend in weight loss, whereby 71.4% of subjects lost weight.
2009	Blum K, et al. [70]	Brain dopamine has been implicated as the so-called “anti-stress molecule.” The present study investigated anti-anxiety effects of Synaptamine Complex [KB220], a dopaminergic activator, in a randomized double-blind placebo controlled study in alcoholics and in polydrug abusers attending an in-patient chemical dependency program. Patients receiving Synaptamine Complex [KB220] had a significantly reduced stress response as measured by SCL, compared to patients receiving placebo.
2010	Braverman ER, et al. [71]	Case study evaluating sustained weight loss with Synaptamine complex in conjunction with Diethypropion (Tenuate ®), hormonal repletion therapy, use of the Rainbow Diet®, and light exercise. After one year, the 58-year-old patient's BMI decreased from 32 to 25.4 kg/m^2 representing a 6.9 kg/m^2 reduction. His body fat composition decreased from 36.91% to 17.8% as measured by the Hologic DEXA scanner.
	Miller DK, et al. [24]	Intravenous Synaptamine complex in protracted abstinence from alcohol and opiates analyzed by qEEG. Report that the qEEGs of an alcoholic and a heroin abuser with existing abnormalities (i.e., widespread theta and widespread alpha activity, respectively) during protracted abstinence are significantly normalized by the administration of 1 intravenous dose of Synaptamine Complex Variant KB220™.
	Blum K, et al. [19]	Protracted Abstinence in Psychostimulant abusers. qEEG analysis in DRD2 A1 allele carriers. Compared to placebo, Synaptose Complex KB220Z™ induced positive regulation of the dysregulated electrical activity of the brain in these addicts.
2011	Blum K, et al. [72]	Synaptamine Complex Variant [KB220]™ as an activator of the meso-limbic system and administration significantly reduces or “normalizes” aberrant electrophysiological parameters of the reward circuitry site. Based on our qEEG studies presented herein, we cautiously suggest that long-term activation of dopaminergic receptors (i.e., DRD2 receptors) will result in proliferation of D2 receptors leading to enhanced "dopamine sensitivity" and an increased sense of happiness. Oral KB220 showed an increase of Alpha activity and an increase low Beta activity similar to 10-20 sessions with Neurofeedback.
2012	Chen D, et al. [73]	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 in detoxified heroin addicts. The results showed that the insomnia and withdrawal scores were significantly improved over time in participants in the intervention group as compared with those in the control group. A greater reduction in tension-anxiety, depression-dejection, anger-hostility, fatigue-inertia and total mood disturbance, and a greater increase in their vigor-activity symptoms were found at day 6 in the intervention group than in the control placebo group.
	Miller M, et al. [14]	In 129 patients, a combination of IV and oral NAAR 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 improvement (P = 0.00001) from pre- to post-treatments: t = 19.1 for Emption, t = 16.1 for Somatic, and t = 14.9 for impaired cognitive. A two-year follow-up in a subset of 23 patients showed: 21(91%) were sober at 6 months with 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. Note: these results of cause do not reflect any other recovery skills utilized by the patients including 12 steps program and Fellowship.
	Blum K, et al. [74]	New Definition of Addiction by American Society of Addiction Medicine (ASAM) is based on concepts related to Reward Deficiency Syndrome (RDS). Brain Reward Cascade (BRC) Impairment leads to aberrant craving behavior and other behaviors such as Substance Use Disorder (SUD) due to a “hypodopaminergic” trait/state. Any impairment due to either genetics or environmental influences on this cascade will result in a reduced amount of dopamine release in the brain reward site. After over four decades of development, neuro-nutrient therapy has provided important clinical benefits when appropriately utilized.
2013	Blum K, et al. [1]	A case study of a 35-year-old female in the film industry with a history of chronic pain from reflex sympathetic dystrophy and fibromyalgia. Total monthly prescription costs including supplemental benzodiazepines, hypnotics, and stimulants exceeded $50,000. Withdrawal symptoms were carefully documented when she precipitously stopped taking buprenorphine/naloxone. At 432 days post Suboxone® withdrawal, the patient is being maintained on KB220Z, has been urine tested and is opioid free. Genotyping data revealed a moderate genetic risk for addiction showing a hypodopaminergic trait.
2015	McLaughlin T, et al. [16]	Lucid dreams may be associated with psychiatric conditions, including Post-Traumatic Stress Disorder (PTSD) and Reward Deficiency Syndrome-associated diagnoses. We present two cases of dramatic alleviation of terrifying lucid dreams in patients with PTSD. The medication visit notes reveal changes in the frequency, intensity, and nature of these dreams after the complex putative dopamine agonist KB220Z was added to the first patient's regimen. The second PTSD patient, who had suffered from lucid nightmares, was administered KB220Z to attenuate methadone withdrawal symptoms and incidentally reported dreams full of happiness and laughter.
	McLaughlin T, et al. [17]	Lucid dreams could be unpleasant or terrifying, at least in the context of patients who also exhibit characteristics of Reward Deficiency Syndrome (RDS) and Post-Traumatic Stress Disorder (PTSD). We present eight clinical cases, with known substance abuse, childhood abuse, and diagnosed PTSD/RDS. The administration of a putative dopamine agonist, KB200Z™, was associated with the elimination of unpleasant and/or terrifying, lucid dreams in 87.5% of the cases presented, whereas one very heavy cocaine abuser showed a minimal response. These results required the continuous use of this nutraceutical. If these results, in a small number of patients are indeed confirmed, we may have found a frontline solution to a very perplexing and complicated symptom known as lucid dreams.
	Blum K, et al. [20]	Willuhn et al. reported that cocaine use and even non-substance-related addictive behavior increases as dopaminergic function is reduced. Chronic cocaine exposure has been associated with decreases in D2/D3 receptors and was also associated with lower activation of cues in occipital cortex and cerebellum, in a recent PET study by Volkow et al. KB220Z induced an increase in BOLD activation in caudate-accumbens-dopaminergic pathways compared to placebo following 1-hour acute administration in abstinent heroin addicts. Increased functional connectivity was observed in a putative network that included the dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. Results suggest a putative anti-craving/anti-relapse role of KB220Z in addiction by direct or indirect dopaminergic interaction.
2016	McLaughlin T, et al. [75]	The four patients initially reported a gradual but, then, complete amelioration of their long-term, terrifying, lucid dreams, while taking KB220Z. The persistent amelioration of these dreams continued for up to 12 months, after KB220Z. These particular cases raise the scientific possibility that KB200Z increases both dopamine stability as well as functional connectivity between networks of brain reward circuitry in both rodents and humans. In order to attempt to understand the possibility of neuroplasticity, we evaluated the effect of KB220Z in non-opioid-addicted rats utilizing functional Magnetic Resonance Imaging methodology. While we cannot make a definitive claim because rat brain functional connectivity may not be exactly the same as humans, it does provide some interesting clues. We did find following seeding of the dorsal hippocampus, enhanced connectivity volume across several Regions of Interest (ROI), with the exception of the pre- frontal cortex. Interestingly, the latter region is only infrequently activated in lucid human dreaming, when the dreamer reports that he/she had the thought that they were dreaming during the lucid dream.
	Harriet Beitscher- Campbell, et al. [76]	While there are still a number of scientists that would argue the commonality between these two seemingly diverse substances, the field is rift with many neuroscience imaging studies that show a neurochemical commonality as well as other genetic studies showing a hypodopaminergic trait. While we did not provide evidence showing any potential difference among those with anorexia nervosa, binge eating disorder, bulimia nervosa, sub-threshold bingeing, we are reporting at a minimum co–morbidity with eating disorders and SUD. Here we show fifty case reports derived from two independent treatment centers in Florida, that suggest the commonality between food and drug addiction.
	Bruce Steinberg, et al. [26]	Attention Deficit-Hyperactivity Disorder (ADHD) often continues into adulthood. Recent neuroimaging studies found lowered baseline dopamine tone in the brains of affected individuals that may place them at risk for Substance Use Disorder (SUD). This is an observational case study of the potential for novel management of Adult ADHD with a non-addictive glutaminergic-dopaminergic optimization complex KB200Z. Low-resolution electromagnetic tomography (LORETA) was used to evaluate the effects of KB220Z on a 72-year-old male with ADHD, at baseline and one hour following administration. The resultant z-scores, averaged across Eyes Closed, Eyes Open, and Working Memory conditions, increased for each frequency band, in the anterior, dorsal, and posterior cingulate regions, as well as the right dorsolateral prefrontal cortex during Working Memory with KB220z. These scores are consistent with other human and animal neuroimaging studies that demonstrated increased connectivity volumes in reward circuitry and may offer a new approach to ADHD treatment. However, larger randomized trials to confirm these results are required.