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Neurogenetics and clinical evidence for the putative activation of the brain reward circuitry by a neuroadaptagen: proposing an addiction candidate gene panel map.

NIDA Director Nora Volkow recently reported that the estimated cost to society of drug abuse in 2002 was $181 billion. Of that figure, $107 billion in costs were associated with drug-related crime. However, according to research conducted in Britain, every dollar spent on addiction treatment results in a four to seven dollar reduction in community spending on drug-related crimes. Moreover, approximately one in 68 (1.47%) or four million people in the USA are addicted to illicit drugs (Schulden, Thomas & Compton 2009). It is well known that addiction to psychostimulants including cocaine is very difficult to treat, having the lowest rate of abstinence compared to alcohol and other drugs (Miller & Gold 1994). The WHO reported a 16% prevalence of cocaine use in the US, more than any other country (Degenhardt et al. 2008). In addition, the prevention and treatment of heroin dependence and alcoholism also constitute a major worldwide concern.

According to the National Survey on Drug Use and Health on the Substance Abuse and Mental Health Administration website (SAMHSA 2009), in 2008, 453,000 Americans age 12 and older had abused heroin at least once in the year prior to being surveyed. The NIDA-funded 2008 Monitoring the Future study showed that 0.9% of eighth graders, 0.8% of tenth graders, and 0.7% of 12th graders had abused heroin at least once in the year prior to being surveyed (Johnston et al. 2009). These statistics are possible due to the purity of the drug and its availability as an inhalant rather than in the injectable form. The National Survey on Drug Abuse found that a large proportion of these new users smoked, sniffed or snorted heroin (SAMHSA 2009).

In 2008, the National Survey on Drug Use and Health (SAMHSA 2009) found that 51.6% of Americans age 12 and older had used alcohol at least once in the 30 days prior to being surveyed; 23.3% had binged (five or more drinks within two hours); and 23.3% drank heavily (five or more drinks on five or more occasions). In the 12 to 17 age range, 14.6% had consumed at least one drink in the 30 days prior to being surveyed, 8.8% had binged, and 2.0% drank heavily.

The NIDA-funded 2008 Monitoring the Future study (Johnston et al. 2009) showed that 15.9% of eighth graders, 28.8% of tenth graders, and 43.1% of 12th graders had consumed at least one drink in the 30 days prior to being surveyed, and 5.4% of eighth graders, 14.4% of tenth graders, and 27.6% of 12th graders had been drunk.

Since the discovery of the double helix, explorations of brain function in terms of both physiology and behavioral traits have resulted in a plethora of studies linking these activities to neurotransmitter functions and demonstrating a genetic basis for addiction. The mechanisms underlining gene expression and the potential impairments due to polygenic inheritance and as such, a predisposition to addiction and self-destructive behaviors have been amply identified. Blum and colleagues (1990) provided the first ever association of a gene polymorphism and addiction to alcohol. The work published in JAMA resulted in an explosion in the field of neuropsychiatric genetics.

Since that time, there have been many articles on the role of Reward Deficiency Syndrome (RDS), as described earlier (Blum et al. 1996)--a syndrome that identifies the influence of genetic antecedents to explain common shared genes related to common addictive behaviors (Bowirrat & Oscar-Berman 2005). We hereby provide important information supporting the role of a novel neuronutrigenomic formula proposed to alter mesolimbic neurochemistry, especially the dopaminergic pathways specific to the nucleus accumbens (NAc). Dopamine is a major component in the mechanisms involving RDS and brain function.

It is well known that certain polymorphisms of a number of reward genes, including the dopamine D2 receptor gene, play a role in the function of dopamine (Blum et al. 1995). RDS seems to be linked to flawed dopamine metabolism and especially to low D2 receptor density (Blum et al. 2008a, b, c, d). Moreover, RDS results from a dysfunction in the mesolimbic system of the brain, which directly links abnormal craving behavior with a defect in the dopamine receptor D2 gene (DRD2) as well as other dopaminergic genes (D1, D3, D4, and D5, DATA1, MAO, COMT), including many genes associated with the brain reward function (Tabakoff et al. 2009).

The role of specific candidate genes has been the subject of much debate and to date, while there is an abundance of compelling evidence, there is no consensus about a unique gene panel for addiction. There are many candidate genes representing the neurochemical mechanisms involved in reward dependence behaviors linked to mesolimbic circuitry. We are therefore proposing one such example of a novel gene panel to determine RDS predisposition (see below).

Most recently, Hodgkinson and colleagues (2008) developed a panel of markers able to extract full haplotype information for candidate genes in alcoholism, other addictions and disorders of mood and anxiety. A total of 130 genes were haplotype tagged and genotyped in seven case/control populations and 51 reference populations using Illumina Golden Gate SNP genotyping technology to determine haplotype coverage.

Other array work has been accomplished by Li and colleagues (2008), who integrated 2,343 items of evidence from peer-reviewed publications between 1976 and 2006 linking genes and chromosome regions to addiction. Using single-gene strategies, microarray, proteomics, or genetic studies they identified 1,500 human addiction-related genes. They developed KARG (http://karg.cbi.pku.edu.cn), the first molecular database for addiction-related genes with extensive annotations and a friendly Web interface. Li and colleagues (2008) then performed a meta-analysis of 396 genes that were supported by two or more independent items of evidence to identify 18 molecular pathways that were statistically significantly enriched, covering both upstream signaling events and downstream effects. Five molecular pathways significantly enriched for all four different types of addictive drugs were identified as common pathways, which may underlie shared rewarding and addictive actions. These included two new ones, GnRH signaling pathway and gap junction. They connected the common pathways into a hypothetical common molecular network for addiction. Interestingly two final pathways emerged: the glutamate pathway and the dopaminergic pathway.

PROPOSED ADDICTION CANDIDATE GENE PANEL

It is noteworthy that very recent studies from Galanter's group at Yale University exploring multiple genotypes and polymorphisms of neurotransmitter pathways found that of all genes involved in substance use disorder (SUD), the most robust association occurred with the DRD2/ANKKI gene loci. Specifically the association with SUD was between [10.sup.-7] to [10.sup.-9] (Li et al. 2009; see Table 1). This panel in part covers a number of genes to be analyzed and constitutes US and foreign patents issued to Kenneth Blum as well as patents pending.

Dopamine is a very powerful neurotransmitter in the brain, which controls feelings of well-being. This sense of well-being results from the interaction of dopamine and neurotransmitters such as serotonin, the opioids, and other powerful brain chemicals. Low serotonin levels are associated with depression. High levels of the opioids (the brain's opium) are associated with a sense of well-being.

Blum and Kozlowski (1990) have termed the complex interactions of these powerful neurotransmitters ultimately regulating the dopaminergic activity in the reward center of the brain the "brain reward cascade."

In individuals possessing an abnormality in the DRD2 gene, the brain lacks enough dopamine receptor sites to achieve adequate dopamine sensitivity and function from the normal dopamine produced in the reward center of the brain. Carriers of the A1 variant in the DRD2 gene tend to be serious cocaine abusers; may have unhealthy appetites and can indulge in overeating, which can lead to altered metabolism and/or obesity. At the other extreme, they can be anorexic with extremely low caloric intake and/or suffer greater consequences of chronic stress. In these individuals, disruption of their neuroendocrine function can lead to high-generalized craving behavior. In essence, they seek substances including alcohol, opiates, cocaine, nicotine, and/or glucose (all substances known to cause preferential release of dopamine at the NActo activate dopaminergic pathways in order to offset their lack of normal D2 receptor numbers, which is caused by the dopamine D2 receptor gene Taq1 A1 allele antecedents (Ritchie & Noble 2003; Comings & Blum 2000; Noble et al. 1991).

It has been found that this genetic polymorphism is associated with abnormally aggressive behavior (Beaver et al. 2007; Chen et al. 2005), which also stimulates the brain's use of dopamine. Not unlike the greater nutrient demands of extreme athletic performance, such excessive behavior exhausts nutrient availability, frustrates gene-nutrient interactions and can results in further aberrant RDS behaviors (like excessive cravings and pleasure seeking), and can also produce a sort of metabolic short circuit.

Dopamine is involved in a number of biological events influencing such factors as bone health, neurological wellness, sex hormone activity, and growth hormone function, among others. RDS involves dopamine resistance, manifesting as a loss of dopamine sensitivity, resulting in a form of sensory deprivation (Blum et al. 2009a) of the brain's reward or pleasure mechanisms, provoking not only central, but other serious peripheral pathway functional consequences. In addition to cellular deficiencies and/or deprivation, the syndrome can manifest in relatively mild or severe behaviors that follow as a consequence of an individual's biochemical inability to derive reward from ordinary, everyday activities. Following the initial discovery by Blum and colleagues (1990b) there have been over 3,058 PUBMED articles on this gene. This genetic variant also is associated with a spectrum of impulsive, compulsive, and addictive behaviors. Thus, the RDS concept unites those disorders and may explain how simple genetic anomalies give rise to complex aberrant behavior.

EVIDENCE FOR THE EXISTENCE OF RDS IN SUBSTANCE USE DISORDER

Blum and colleagues (1990), using the Taq1 polymorphism of the dopamine D2 receptor gene locus (DRD2), reported a strong association between a virulent form of alcoholism and the minor allele (A1) of the DRD2 gene in this population. Other more recent studies further support an association of the A1 allelic form of the DRD2 gene with substance abuse vulnerability (including heroin) and other compulsive behaviors (Vereczkei, Sasvari-Szekely & Barta 2009; Xu et al. 2004). This association serves as the cornerstone of the biogenetic disease model, which points us toward better diagnosis and more effective targeted treatment protocols. A complete review of this work can be found in the following reviews providing evidence for the need to stimulate D2 receptors in the treatment of RDS (Le Foll et al. 2009; White et al. 2009; Noble 2000). Although debatable, it is our notion that the real genesis of all behavior, whether so-called normal (socially acceptable) or abnormal (socially unacceptable) behavior, derives from an individual's genetic makeup at birth. This predisposition, due to multiple gene combinations and polymorphisms, is expressed differently based on numerous environmental elements including family, friends, educational and economic status, environmental contaminant exposure, and the availability of psychoactive drugs and food. We believe the core of predisposition to these behaviors is a set of genes that promote a feeling of well-being via neurotransmitter interaction at the "reward site" of the brain (located in the mesolimbic system), leading to normal dopamine release and influencing dopamine receptor density. The DRD2 gene is responsible for the synthesis of dopamine D2 receptors. And, further depending on the genotype (allelic form A1 versus A2), the DRD2 gene dictates the number of these receptors at post-junctional sites.

A low number of D2 receptors (Hirvonen et al. 2009; Noble et al. 1991) suggests a hypodopaminergic function in addictive disorders and attention deficit hyperactivity disorder (ADHD) as described by Volkow and colleagues (2009) in a series of published works, as well as by Garner's group (Xi et al. 2009). When there is a paucity of dopamine receptors, the person will be more prone to seek any substance or behavior that stimulates the dopaminergic system (a sort of "dopamine fix").

In this regard, Qing-Shan Yan (2002) reported that ethanol, at a peak concentration within five to ten minutes after interparenteral administration, significantly increased both extracellular dopamine and serotonin in the NAc, supporting the role of these two neurotransmitters in the reinforcing properties of ethanol. Moreover, Honkanen and associates (1997) also found low basal dopamine release in alcohol accepting (AA) compared to alcohol nonaccepting (ANA) rats, showing that dopamine plays a role in high alcohol preference of AA rats.

Three important reports from Nora Volkow's group further provides support for the role of the dopamine D2 receptor gene in alcohol intake in rats (Thanos et al. 2005, 2004, 2001). Utilizing a cDNA construct of the dopamine D2 receptor gene implanted into the NAc of rats, they found that following a four-day treatment, dopamine D2 receptors increased to 150% above pretreatment level and alcohol drinking was reduced by 50%. After a period of eight days, the D2 receptor density returned to pretreatment level and so did alcohol drinking. Twenty-four days later, second injections of the same construct caused a similar increase in density with a two-fold decrease in drinking. The same group confirmed this work in mice. Moreover, Thanos and colleagues (2008) found that dopamine D2 receptor vector treatment resulted in a significant decrease (75%) in cocaine infusions and lever presses (70%) for cocaine. This effect lasted six days before cocaine consumption returned to baseline levels, which corresponds roughly to the time it takes Dopamine D2 receptor to return to baseline levels. These findings show that cocaine self-administration and dopamine D2 receptors in the NAc are negatively correlated and suggest that cocaine intake is modulated in part by dopamine D2 receptor levels in NAc. Thus strategies aimed at increasing dopamine D2 receptor expression in NAc may be beneficial in treating cocaine abuse and addiction.

REWARD GENES AND THE ADDICTIVE BRAIN

Dopaminergic genetic anomalies previously found to be associated with alcoholism (Blum et al. 1990) are also found among people with other addictive, compulsive, or impulsive conduct disorders. The list is long, remarkable, and comprises overeating and obesity, Tourette syndrome, attention deficit disorder (ADD), and pathological gambling, among others. We believe these disorders are linked by a common biological substrate, a "hard-wired" system in the brain (consisting of cells and signaling molecules) that provide pleasure in the process of rewarding certain behavior. Consider how people respond positively to safety, warmth and a full stomach. If these needs are threatened or are not being met, we experience discomfort and anxiety (Blum et al. 2007c).

Moreover, the immune and neuroendocrine systems are intricately "wired" into sensing and responding to the stress and survival threats triggered by various aspects of this process and are also directly influenced by dopamine. An inborn chemical imbalance that alters the intercellular signaling in the brain's reward process could supplant an individual's feeling of well-being with anxiety, anger, or a craving for a substance that can alleviate the negative emotions. It is also known that deficiencies in endorphinergic pathways influence one's immune response, which induces abnormalities in a number of aproimetric parameters (Li et al. 2009). Genotyping patients for a number of dopaminergic and other gene polymorphisms (i.e. serotonergic, endorphinergic, clock, etc.) will be informative and could help explain neurological deficits during protracted abstinence and even provide insight on how to curtail future substance use.

In terms of heroin withdrawal, Li and colleagues (2009) evaluated outcome measures relative to the expression of clock gene mRNA (hperiod1, hperiod2, hclock) and the levels of serum cortisol, plasma ACTH, beta-endorphin (beta-EP), leptin, neuropeptide Y, interleukin-2 (IL-2), and tumor necrosis factor (TNF) in these subjects. Compared with healthy volunteers, abstinent addicts showed disruptions in diurnal rhythms of hPER1 and hPER2 mRNA expression, along with disruptions in diurnal rhythms of cortisol, ACTH, beta-endorphin, leptin, and IL-2 release. Several of these disruptions (hPER1, hPER2, ACTH, beta-endorphin, and IL-2) persisted for the 30-day testing period, as did elevation of 24-hour levels of cortisol and decreases in 24-hour IL-2 and TNF levels. These prolonged neurobiological changes may play a role in protracted opiate withdrawal symptoms and contribute to relapse vulnerability, and may affect brain reward circuitry.

Animal model research that supports the cascade theory (Blum & Kozlowski 1990) include a series of experiments carried out by T.K. Li and colleagues (Lee et al. 2009a) on their substance-preferring (P; seek carbohydrates, alcohol, opiates, etc.) and nonpreferring (NP) rat lines. They found that P rats have the following neurochemical profile:

* lower serotonin neurons in the hypothalamus

* higher levels of enkephalin in the hypothalamus (due to a lower release of serotonin)

* more GABA neurons in the nucleus accumbens (NAc)

* reduced dopamine supply at the NAc

* reduced densities of dopamine D2 receptors in the mesolimbic areas

* Reduced salsolinol [the tetrahydroisoquinoline derivative]

This suggests a six-part cascade sequence leading to a reduction of net dopamine release in a key reward area. This was further confirmed when Ding and colleagues (2009) demonstrated reduced craving behavior by administering substances that increase the serotonin supply at the synapse, or by directly stimulating dopamine D2 receptors. Specifically, D2 receptor agonists reduce alcohol intake in high alcohol-preferring rats, whereas D2 dopamine receptor antagonists increase alcohol drinking in these inbred animals--a finding related to blocking of GABA sites. The finding of low levels of both salsolinol and dopamine in the NAc of P rats compared to NP rats supports the original work of Blum's group (Blum et al. 1982).

It is well known that enkephalinergic pathways play a pivotal role in addictive behavior. In this regard, Blum and colleagues (1987) reversed alcohol-seeking behavior in genetically preferring C57Bl/6J mice with the chronic administration of an enkephalinase inhibitor. In other work by George and colleagues (1991), they concluded that a relative lack of enkephalin peptides trans-synaptically, possibly resulting from enhanced enkephalin degradation, might contribute to increased alcohol consumption in C57Bl/6J mice. Moreover, others showed that intracranial self-stimulation by rats was reduced by NAc microinjections of kelatrophan, a potent enkephalinase inhibitor and chronic D2 receptor blockade that is protective by kelatorphin (Maldonado et al. 1990).

BRAIN HYPODOPAMINERGIC FUNCTION AND THE PSEUDO SELF-HEALING PROCESS

Since deficits have been found in neurotransmitter functions underlying craving behavior, and since these deficits may be alleviated by facilitated dopamine release consequent to the use of opiates, nicotine, alcohol, and food, the studies mentioned above indicate enkephalinase inhibition may similarly compensate for neurotransmitter imbalance (i.e., opioids, thereby attenuating craving behavior). To understand generalized craving behavior due to hypodopaminergic function (an impaired "reward cascade"), scientists believe individuals self-heal (or self-medicate) through biochemical (illicit or nonillicit) attempts to alleviate the low dopaminergic brain activity via drug-receptor activation (alcohol, heroin, cocaine, and glucose). It is conjectured that this will substitute for the lack of reward and yield a temporary compensatory sense of well-being. In order to help explain this so-called pseudo self-healing process, it is germane that the reinforcing properties of many drugs of abuse may be mediated through activation of common neurochemical pathways, particularly with regard to the mesolimbic dopamine system. In predisposed genotypes, gene polymorphic expression (and resulting aberrant behavior) is amplified in response to chronic nutritional deficiencies from habitual dietary patterns that are chronically unable to meet the greater nutrient needs mandated by those polymorphisms (manifesting as RDS). In this regard, glucose, opiates, nicotine, cocaine, tetrahydrocannibinol (THC), and ethanol have been shown to directly or indirectly enhance release or block re-uptake of dopamine in at least one of the primary terminal sites for the limbic dopamine neurons, the NAc. These findings suggest the importance of genotyping for polymorphisms of the dopaminergic and other reward pathways to develop a genetic positioning system map (GPS) for each individual (Downs et al. 2009).

REWARD DEFICIENCY SYNDROME: HUMAN STUDIES

Human research that supports the RDS mechanism for addictive behaviors can be derived from imaging experiments (Table 2) and a series of clinical trials (Table 3) with nutraceuticals (precursor amino acid loading technique and enkephalinase inhibition) indicating:

* Reduced alcohol and cocaine craving

* Reduced stress rates

* Reduction of leaving treatment against medical advice (AMA)

* Facilitated recovery

* Prolonged abstinence and reduced relapse rates

* Reduction in carbohydrate bingeing

* Loss of body weight

* Prevention of weight regain

* Reduction of glucose craving

* Enhancement of insulin sensitivity (reversal of metabolic syndrome X)

* Reduction of cholesterol

* Enhancement of memory and focus

* Enhanced compliance with narcotic antagonists

* Increased energy

* Enhanced sense of happiness

* qEEG studies reveal both IV and oral administration reduce qEEG abnormalities of the brain and also increase alpha bands with concomitant increase in low beta bands (see Table 2)

* Preliminary evidence using oral dosage shows that experimental vs. placebo activates the caudate regions of the brain from resting state fMRI studies (see Table 2)

There are a number of studies using precursor amino acids and enkephalinase inhibition that have been shown to affect various aspects of RDS (Miller et al. 2010; Blum, Chen & Chen 2009; Blum et al. 2008b, c; Blum et al. 2007b, c; Blum & Kozlowski 1990; Blum et al. 1990b; Brown, Blum & Trachtenberg 1990; Blum et al. 1988a,b; Blum, Trachtenberg & Ramsay 1988; see Table 3 and Figure 1). Basically all of these studies evaluated the efficacy of KB220/KB220Z variants we term neuroadaptogen amino acid therapy (NAAT).

[FIGURE 1 OMITTED]

NEUROADAPTAGEN AMINO-ACID THERAPY (NAAT)

According to Mosby's Dictionary of Complementary and Alternative Medicine (Jonas 2004), an "adaptogen" is a substance that helps the body regenerate after being fatigued or stressed. It is a homeostatic agent. A neuroadaptogen is an adaptogen that is used to regenerate neurological deficits and increase the brain's and nervous system's resistance to stress, trauma, anxiety, fatigue and chemical imbalances. KB220 and KB220Z are neuroadaptogens that utilize evidence-based amounts of specific amino acids along with vitamins, minerals, and select botanicals to effect therapeutic neuroadaptogenic regeneration. The basic NAAT formula included amino acid precursors such as L-phenylalanine, l-tyrosine, L-tryptophan, 5-hydroxytryptophane, L-glutamine (a serotonin concentrating substance), chromium (an enkephalinase inhibitor), D-phenylalanine (a neurotransmitter synthesis promoter), vitamin B6, Rhodiola rosea and both methionine and leucine (see Table 4).

[FIGURE 2 OMITTED]

In one study using intravenous administration of a NAAT variant in 600 alcoholics and polysubstance abusers we found significant results in terms of reducing many RDS behaviors. Figure 2 illustrates our previously published findings (Blum et al. 2007b).

In an unpublished study we evaluated KB220IV along with oral variants directed to overcoming hypodopaminergic function. In our first experiment we found a significant reduction of chronic symptoms as measured by the Chronic Abstinence Symptom Severity [CASS] Scale (unpublished) for both IV and oral compared to only oral administration. Specifically, the IV and oral group did significantly better than the oral only group over the first week as well as over the 30-day period. In the second experiment consisting of 129 subjects receiving both IV and orals three factors with eigenvalues greater than one were extracted for the baseline CASS variables. Three scales were constructed based on this factor analysis: Emotion, Somatic, and Cognitive. Paired sample t-tests between the pretreatment scales and the post-treatment scales were calculated. 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 Cognitive. In a two-year follow-up on 23 subjects who underwent KB220IV therapy plus orals for at least 30 days, 21 (91%) were sober at six months with 19 (82%) having no relapse, 19 (82%) were sober at one year with 18 (78%) having no relapse, and 21 (91%) were sober at two years post-treatment with 16 (70%) having no relapse. Awaiting additional required research, we cautiously propose that KB220IV therapy (a putative dopaminergic agonist) may provide important therapeutic outcomes in residential treatment program.

To date, while there are a number of clinical trials using amino acid precursors and enkephalinase inhibition that support the beneficial effects of this putative dopaminergic agonist (e.g. D2 receptor activation), there is a paucity of information related to the direct interaction of this proposed nutraceutical at mesolimbic reward circuitry loci. Most recent experiments have also incorporated Rhodila rosea for its effect on brain monoamines and both MAO and COMT inhibition (Blum et al. 2007a; van Diermen et al. 2009).

DOPAMINE SYNTHESIS AND NUTRIENT THERAPY

There are a number of choices in terms of nutrient therapy that affect dopaminergic function; not all involve amino acids. Many reports in recent years have shown that the intake of polyunsaturated fatty acids (PUFA) constitutes an environmental factor able to act on the central nervous system (CNS) function. Chalon's group (Zimmer et al. 2002; Chalon et al. 1998) demonstrated that the effects of PUFA on behavior can be mediated through effects on the monoaminergic neurotransmission processes. Supporting this proposal, they showed that chronic dietary deficiency in alpha-linolenic acid in rats induces abnormalities in several parameters of the mesocortical and mesolimbic dopaminergic systems. In both systems, the pool of dopamine stored in presynaptic vesicles is strongly decreased. This may be due to a decrease in the number of vesicles.

These neurochemical changes are in agreement with modifications of behavior already described with RDS. The precise mechanisms explaining the effects of PUFA on neurotransmission remain to be clarified. For example, modifications of physical properties of the neuronal membrane, effects on proteins (receptors, transporters) enclosed in the membrane, and effects on gene expression and/or transcription might occur. Whatever the mechanism, it is therefore assumed that interactions exist among PUFA, neurotransmission, and behavior. This might be related to clinical findings. Indeed, deficits in the peripheral amounts of PUFA have been described in subjects suffering from neurological and psychiatric disorders. Involvement of the monoaminergic neurotransmission function has been demonstrated or hypothesized in several of these diseases. It can therefore be proposed that functional links exist among PUFA status, neurotransmission processes, and behavioral disorders in humans.

Specifically, supplemental Omega 3 Essential Fatty Acids, specifically DHA, can lead to an up-regulation in dopamine 2 receptors. A deficiency in Omega 3 EFA, and/or dominance of COX and LOX enzyme pathways by Omega 6 fatty acids (linoleic acid and arachidonic acid) can lead to increased pro-inflammatory TNF, Interleukin-1, and Interleukin-6. Moreover, high dietary levels of Omega 6 fatty acids leads to excessive production of prostaglandin E-2 which is not only inflammatory, but leads to decreased neural integrity and fluidity (Chalon et al. 1998).

Moreover it is well-known that supplementation of L-tyrosine and or L-tryptophan or even foods rich in these rate-limiting amino acids can increase the synthesis of neuronal dopamine and serotonin respectively (Wurtman et al. 2003). The delivery of circulating tryptophan to the brain and its conversion to serotonin vary directly with plasma concentrations of tryptophan and inversely with those of other large neutral amino acids (LNAAs). Although carbohydrate-rich, protein-free formula diets have been shown to elevate, and high-protein diets to depress, the tryptophan-LNAA ratio, few data are available about this ratio's responses to actual meals. High-carbohydrate and high-protein breakfasts similar to those Americans normally eat can cause substantial differences in the plasma tryptophan ratio and thus, probably, in brain tryptophan concentrations and serotonin synthesis. Such meals also change the plasma tyrosine ratio and may thereby modify catecholamine synthesis (Fortuna 2009; Fernstrom & Wurtman 1975).

Moreover, an Omega 3 EFA supplement (docosahexanoic acid) should also be considered, to up-regulate cyclic ATP and adenylate cyclase activity in dopaminergic neurons within the nucleus accumbens and other midterm structures. Separately, the Omega 3 EFA increase the integrity and fluidity of phospholipids membranes throughout the brain which translates to an enhanced brain function via up-regulation of dopamine D2 receptors (Price & Tisdale 1998).

NEUROIMAGING RATIONALE AND PRELIMINARY RESULTS

In order to determine the putative role of NAAT on brain reward circuitry (caudate-putamen-NAc, corticofrontal and parietal lobes) we embarked on series of preliminary studies. These studies for the most part are in progress and continuing. The studies involve both qEEG and fMRI, and based on our approved IRB protocol (University of Florida College of Medicine, and Beijing University Medical School and PATH Foundation NY); each participant signed an approved consent form.

Alcoholism

There are 18 PUBMED publications regarding qEEG and alcoholism during different phases of the disease. It is well known that biofeedback has been a useful tool in the treatment of tertiary alcoholism, for example using the alpha-theta training approach where the goal is to increase alpha activity while also increasing low beta activity. Moreover, electroencephalographic (EEG) biofeedback has been employed in substance use disorders (SUD) over the last three decades (Peniston & Kulkosky 1989). The SUD is a complex series of disorders with frequent comorbidities and EEG abnormalities of several types. EEG biofeedback has been employed in conjunction with other therapies and may be useful in enhancing certain outcomes of therapy. Based on published clinical studies and employing efficacy criteria adapted by the Association for Applied Psychophysiology and Biofeedback and the International Society for Neurofeedback and Research, alpha theta training--either alone for alcoholism or in combination with beta training for stimulant and mixed substance abuse and combined with residential treatment programs--is probably efficacious.

Newer advances have been reported in terms of EEG training. One such example is that of virtual reality therapy (VRT). Alcoholism is a disease that affects parts of the brain that control emotion, decisions, and behavior. Therapy for people with alcoholism must address coping skills for facing high-risk situations. Therefore, it is important to develop tools to mimic such conditions. Cue exposure therapy (CET) provides high-risk situations during treatment, which raises the individual's ability to recognize that alcohol craving is being induced. Using CET, it is hard to simulate situations that induce alcohol craving. By contrast, virtual reality (VR) approaches can present realistic situations that cannot be experienced directly in CET. It has been shown by Cho and colleagues (2008) that by developing a VRT system including social pressure that subsequent alcohol craving increased over no VRT. In studies published by the same group (Lee et al. 2009b) on alcohol dependence (AD), the VRT-AD exhibited a greater decrease in craving after the tenth VRT session, when compared to the non VRT-AD. Compared to the healthy control subjects, VRT-AD group showed a higher magnitude of the change in craving throughout VRT sessions. This work is compatible with Peniston's alpha-theta training (Graap & Freides 1998).

Fahrion and colleagues (1992) reported on the benefits of alpha-theta training in alcoholism. They concluded that there were post-treatment indications of more relaxed CNS functioning under stress and of reduced autonomic activation, both during relaxation and under stress. At four months post biofeedback treatment, the patient's wife and colleagues reported that the patient appeared to function in a more relaxed way under the impact of stress, and the AD patient reports no longer experiencing craving for alcohol. Overall, support is provided for the possibility that alpha and theta brainwave training may be a useful intervention for the abstinent alcoholic experiencing stress-related craving and fear of relapse. This is further supported by others (Sokhadze et al. 2008).

To date, while there are a number of clinical trials using amino-acid precursors and enkephalinase inhibition, which support the beneficial effects of this putative dopaminergic agonist (e.g. D2 receptor activation), there is a paucity of information related to the direct interaction of this proposed nutraceutical at mesolimbic reward circuitry loci. The design of our experiment was to preliminarily evaluate the acute intravenous administration of NAAT in alcohol protracted abstinence patients. The purpose was to determine the potential of normalizing aberrant neurological deficits in mesolimbic reward circuitry loci by utilizing qEEG analysis.

EEG Analysis Explanation

Abundant research has established that the electroencephalogram (EEG) recorded from a healthy, normally functioning human has a predictable distribution of electrical power (measured in microvolts squared), just as does the electrocardiogram, or EKG. These predictable electrical signals, distinctive for each brain region, are regulated by the homeostasis of a complex neuroanatomical brain system that utilizes all known neurotransmitters. Just as the EKG can be used to assess heart dysfunctions, the EEG can assess a wide variety of brain dysfunctions related to developmental, neurological and psychiatric disorders, whether caused by structural or functional abnormalities; this is called EEG analysis. Quantitative electroencephalography (qEEG) measures brain wave activity numerically and displays the results in a colored map of brain function. This measurement is quantitative as opposed to strictly qualitative in that a predetermined standard of normal brain activity is used as a baseline, and the colors of the map indicate deviations from this norm. For example, the color red indicates excessive activity while blue is indicative of slow brain activity. Particular disorders manifest themselves in particular parts of the brain, and thus can be identified in the activity or lack thereof in these areas. In cases such as addiction, impulsivity, and depression, specific patterns of brain activity have been identified.

A detailed report will be found in a pilot series case study (Miller et al. 2010) employing nineteen electrodes using an electro-cap consistent with the International 10/20 systems were placed. Routine EEG was recorded on a Cadwell Easy II using a linked ear montage and with electrodes digitally referenced to the Cz electrode, allowing for retrospective montage analysis of all data. Using data gathered under technical conditions as listed above, 99.24 seconds of EEG were selected and subjected to quantitative analysis of absolute power, relative power, power asymmetry and coherence. These measurements are logarithmically transformed and referenced to age-adjusted population norms.

Psychostimulant Dependent Subjects

Earlier studies by Noble and colleagues (1993) showed that the prevalence of the DRD2 A1 allele in cocaine dependent (CD) subjects (n = 53) was 50.9%. It was significantly higher than either the 16.0% prevalence (p < [10.sup.-4)] in nonsubstance-abusing controls (n = 100) or the 30.9% prevalence (p < [10.sup.-2]) in population controls (n = 265) wherein substance abusers were not excluded. Logistic regression analysis of CD subjects identified potent routes of cocaine use and the interaction of early deviant behaviors and parental alcoholism as significant risk factors associated with the A1 allele. The cumulative number of these three risk factors in CD subjects was positively and significantly (p < [10.sup.-3]) related to A1 allelic prevalence. A later follow-up by Daunais and McGinty (1996) to this robust association supported the role of DRD2 genotype and cocaine abuse.

In a study by Daunais & McGinty (1996), selective D1 or D2 dopamine receptor antagonists were used to investigate the transynaptic regulation of mRNAs coding for the opioid peptide, preprodynorphin, and the nuclear transcription factor, zif/268 after an acute cocaine binge. They found the substances SCH 23390 and sulpiride blocked cocaine binge-induced expression of preprodynorphin mRNA in the dorsal striatum. The data also shows a strong association of the minor alleles (A1 and B1) of the DRD2 with cocaine dependence, suggesting that a gene located on the q22-q23 region of chromosome 11 confers susceptibility to this drug disorder.

There have been a number of studies showing persistent qEEG abnormalities in crack cocaine users in general (Newton et al. 2003; Roemer et al. 1995) and at six months of drug abstinence (Alper et al. 1998). However, as far as we know there are no documented papers showing "normalization" of qEEG abnormalities following acute administration of any biological/pharmaceutical agent except by cocaine itself (Reid et al. 2006). Moreover, there are only two Pubmed studies on the relationship of genes and qEEG (Lehtovirta et al. 2000; Jelic et al. 1997), none of which relate to reward dependence behaviors.

Due to the paucity of information related to persistent qEEG cortical brain abnormalities and reward gene polymorphisms (e.g. DRD2 etc.), we decided to genotype psychostimulant abusers undergoing protracted abstinence for at least a six-month period for a number of reward gene polymorphisms and to access for a potential association of qEEG cortical brain abnormalities with these known candidate polymorphisms. In addition, but also important, we also decided to evaluate the acute oral effect of a putative natural D2 agonist known from earlier studies to have multiple positive clinical antistimulant/psychoactive properties (see Table 1) on persistent qEEG cortical brain abnormalities. These studies are in progress but the initial results are worth noting in this review.

Oral NAAT: A Study

We decided to test the acute oral NAAT on reward circuitry during protracted abstinence following psychostimulant dependence in ten subjects associated with G & G Holistic Addiction Treatment Center of North Miami Beach, Florida. These subjects were diagnosed as having severe psychostimulant dependence and have been in recovery for at least two years. As part of the inclusion criteria, each patient was urine tested to determine the absence or presence of any illicit psychoactive drug. None of the subjects tested showed a positive drug tested urine. Therefore, they were subsequently admitted to the study.

To date in preliminary analysis we have found that a comparison of the FFT absolute power (uVSq) of alpha (8-12Hz) demonstrated higher activity in the NAAT group compared to the placebo group. Similarly observing the FFT absolute power (uVSq) of low beta (12.0 15hz), the activity is considerably larger in the NAAT group compared to the placebo group. Finally, there was a consistent effect of NAAT on frontal regions when compared to placebo. The p values for group 1 (NAAT) versus group 2 (placebo) for a between-group analysis of week 1 and week 2 whereby group comparisons utilizing T-tests were performed resulted in significant differences. This study is still in progress whereby we are increasing the subject population (see Table 2). The results of this preliminary study has been recently published (Blum et al. 2010a).

There are numerous clinical trials showing various recovery benefits from RDS behaviors using NAAT. However, prior to the imaging studies, a measurable magnitude of effect and the mechanism of action have been elusive. The results of these preliminary qEEG studies suggest an interaction of NAAT and mesolimbic activation leading to "normalization" of abnormal dopaminergic function in anticipation of patients carrying a number of reward gene polymorphisms.

While NAAT appears to be a D2 natural nonaddicting agonist, cautious interpretation must await future fMRI and PET scan analysis to determine chronic induction of D2/D3 receptors, especially in DRD2 A1 allele carriers and direct interaction at D2 receptor NAc interaction. We are performing additional qEEG experiments using a larger sample size to further confirm these findings.

Further confirmation and study expansion results of the qEEG analyses and continued demonstration that NAAT in the oral form leads to activation of the parietal and frontal regions of the brain will be important. Moreover, increasing both alpha and low beta activity will have important clinical outcomes. If confirmed it will suggest that NAAT "normalizes" brain abnormalities associated with drug dependence (alcohol, heroin and psychostimulants) induced by dopaminergic deficiency by acting as a dopaminergic receptor agonist during protracted abstinence in polydrug abusers. This notion is supported by other studies showing enhanced treatment response in only A1 vs. A2 carriers (Ooteman et al. 2009; Blum et al. 2008d; Lawford et al. 1995). We anticipate that the greatest effect will have occurred with those individuals possessing the DRD2 TAQ A1 allele.

We cautiously suggest that long-term activation of dopaminergic receptors (i.e., DRD2 receptors) will proliferate D2 receptors leading to enhanced "dopamine sensitivity" and an increased sense of happiness. Even in carriers of DRD2 A1 allele in psychostimulant abusers (Noble et al. 1993) this is supported by numerous clinical trials and awaits PET scanning results to determine chronic effects of NAAT on numbers of D2 receptors. Positive outcomes will provide important information that could ultimately lead to significant improvement of recovery for victims of RDS having dopamine deficiency (Chen et al. 2008; Bowirrat & Oscar-Berman 2005; Noble 1991; Trachtenberg & Blum, 1988; Dackis & Gold 1985).

Opiate Dependence

In earlier studies we showed significant improvement in a number of RDS related behaviors in over 600 poly-substance abusers (including heroin addicts) treated with the IV NAAT variant (Blum et al. 2007b) as well other studies using oral doses of the NAAT variant (Chen et al. 2004). There are many studies (21 in PUBMED) showing the relationship of dopaminergic genes and heroin addiction (Crettol et al. 2008). In one study, polymorphisms of the DRD2 gene were associated not only with a risk of heroin dependence but could contribute to our understanding of the inter-individual variability of the response to methadone maintenance treatment compliance (Crettol et al. 2008). These data may help explain the enhanced treatment compliance we obtained with the addition of the NAAT variant to treatment with naltrexone in methadone addicts (Chen et al. 2004). This is further supported by the work of Lawford and colleagues (2000).

Striatal enkephalin and dynorphin opioid systems mediate reward and negative affect, respectively, and are relevant to addiction disorders. Experiments have shown polymorphisms of proenkephalin (PENK) and prodynorphin (PDYN) genes are related to heroin abuse and gene expression in the human striatum. These in turn are relevant to genetic dopaminergic tone, critical for drug reward and striatal function. Control COMT Met/Met individuals expressed lower PENK mRNA than Val carriers, a pattern reversed in heroin users. Up-regulation of NAc PENK in Met/Met heroin abusers was accompanied by impaired tyrosine hydroxylase (TH) mRNA expression in mesolimbic dopamine neurons (Nikoshkov et al. 2008).

While it is generally accepted that there are common gene polymorphisms between cocaine and heroin especially in dopaminergic transmission there are also distinctive nonsharing genes differentially expressed in these two seemingly common drug abuse cohorts. Nevertheless since there are at least 25 common gene expressions, the singular use of a common treatment with some modification maybe parsimonious (Albertson et al. 2006).

Most importantly, heroin dependence results from the interaction between multiple genetic and environmental factors. Subjective craving is considered to be a central phenomenon, which contributes to the continuation of drug use in active abusers and the occurrence of relapse in detoxified abusers. The dopamine pathway has been implicated in the cue-elicited craving for a variety of addictive substances. The objective of a study by Li and colleagues (2006) was to test the hypothesis that heroin addicts carrying specific variants in dopamine-related genes would have higher levels of craving following exposure to a heroin-related cue. Craving induced by a series of exposures to heroin-related cue was assessed in a cohort of Chinese heroin abusers (n = 420) recruited from a natural abstinence center at Shanghai. Significantly, stronger cue-elicited heroin craving was found in individuals carrying D2 dopamine receptor gene (DRD2) TaqI RFLP A1 allele than the non-carriers (p < 0.001). Furthermore, the authors did not observe significant association of cue-elicited craving with the nine-repeat allelic variants in dopamine transporter gene (DAT) SLC6A3 and with the dinucleotide repeat polymorphism (DRP) 148bp allele in D5 dopamine receptor gene (DRD5). The results of their study suggest that the human dopamine pathway is involved in cue-induced heroin craving, and indicate a potential genetic risk factor for persistent heroin behavior and relapse.

Numerous studies have documented cognitive impairments and hypoactivity in the prefrontal and anterior cingulate cortices in drug users. However, the relationships between opiate dependence and brain structure changes in heroin users are largely unknown. Yuan and colleagues (2009) measured the density of gray matter (DGM) with voxel-based morphometry in 30 lifetime heroin-dependent individuals who had abstained from drug use for 5 months, and 34 healthy participants. The DGM of the prefrontal, temporal and cingulate cortices significantly decreased in heroin addicts relative to the healthy group. Critically, partial correlation analysis, which controlled for age, education and gender factors as well as nicotine use and heroin abstinence duration, showed that the duration of heroin use negatively correlated with the DGM in heroin-dependent individuals.

These results provide compelling evidence for structural abnormality in heroin-dependent individuals and further suggest that duration of heroin use is a critical factor leading to brain damage.

It is widely accepted that addictive drug use is related to abnormal functional organization in the user's brain. A study by MA and colleagues (2010) aimed to identify this type of abnormality within the brain networks implicated in addiction by resting-state functional connectivity measured with fMRI. With fMRI data acquired during resting state from 14 chronic heroin users (12 of whom were being treated with methadone) and 13 non-addicted controls, they investigated the addiction-related alteration in functional connectivity between the regions in the circuits implicated in addiction with seed-based correlation analysis. Compared with controls, chronic heroin users showed increased functional connectivity between nucleus accumbens and ventral/rostral anterior cingulate cortex (ACC), between NAc and orbital frontal cortex (OFC), and between amygdala and OFC and reduced functional connectivity between prefrontal cortex and OFC and between prefrontal cortex and ACC. These observations of altered resting-state functional connectivity suggested abnormal functional organization in the addicted brain and may provide additional evidence supporting the theory of addiction that emphasizes enhanced salience value of a drug and its related cues, but weakened cognitive control in the addictive state (Liu et al. 2009). Moreover, heroin-dependent individuals compared to nondependent controls had an impaired response inhibition function that lasted even months into abstinence, which indicates that the negative effect of heroin on the inhibitory function still continues in early protracted withdrawal state (Fu et al. 2008).

It is noteworthy that heroin administration reduces brain activation as measured by fMRI. This may be important during detoxification of the heroin addict (Sell et al. 1997). It has been previously postulated that some of the of the neurologic and psychiatric complications of drug abuse and in particular heroin may be due to its effects on the cerebral circulation (Volkow, Valentine & Kulkarni 1988). Finally it has been reported that morphine withdrawal leads to reduced dopamine D2 receptors in the caudate putamen, NAc shell, NAc core, substantia nigra and medial globus pallidus (Zhou et al. 2004).

NAAT IV Therapy in Heroin Patients

The purpose of this case was to preliminarily evaluate the acute intravenous administration of KB220Z in opiate protracted abstinence patients to determine the potential of normalizing aberrant neurological deficits in meso-limbic reward circuitry loci by utilizing quantitative electroencephalographic (qEEG) analysis. The basic protocol was the same as described earlier with the alcoholic patient (Miller et al 2010).

A 24-year-old male with a history of opiate addiction was used to determine the effect of KB220 IV on qEEG response. The subject was medication and drug free for 30 days prior to the study. A baseline qEEG was performed, followed by a three-hour IV amino acid drip. Approximately 45 minutes after the IV drip a post treatment qEEG was performed. Post intravenous amino acid treatment decreased widespread theta at 4-7hz and at 15-16hz indicating improved functioning (see Table 2 and Miller et al. 2010).

PRELIMINARY fMRI HEROIN STUDIES IN CHINA

Oral NAAT Vs Placebo

This study has an ongoing 2X2 design using fMRI at rest and during cue tasks. Each subject was treated with either NAAT or a matched placebo and then one week later crossed. The resultant data is only related to the resting state and preliminary data illustrates that just one dose of NAAT post oral amino acid treatment induces activation at the caudate-putamen (a site of emotionality)-NAc brain regions. There is also the possibility that these data also illustrate a reversal of putamen abnormalities following heroin abuse. Details related to significance must await further testing, which will also include cue-induced craving behavior (see Table 2)

Moreover, in future experiments we plan to evaluate the potential of NAAT to correct the blunted response in the striatum and orbitofrontal cortex to intake of palatable food and imagined intake (respectively) that is associated with the DRD2 A1 allele in humans, as reported by Stice and colleagues (2008). Overcoming the blunted response with any psychoactive substance to palatable food will reduce overeating, ultimately induce weight loss, and foster an enhanced sense of happiness--a worthy goal affecting over 100 million people in the US alone (and millions more around the globe) that should impact standards of care worldwide.

CONCLUSION

While there is support for a higher likelihood of treatment response and compliance using dopaminergic agonist therapy in carriers of the DRD2 A1 allele (utilizing nutrigenomic principles) compared to DRD2 A2 allele genotype by several investigators, the actual mechanism for positive clinical outcomes remains a mystery (Peng et al. 2010; Blum et al. 2009b).

For the first time in the history of this work involving dopaminergic genetics, Laakso and colleagues (2005) have provided a clue. Accordingly, the A1 allele of the TaqI restriction fragment length polymorphism (RFLP) of the human dopamine D2 receptor gene (DRD2) is associated with a low density of D2 dopamine receptors in the striatum. Because of the important role of D2 autoreceptors in regulating dopamine synthesis, they aimed to examine whether subjects with the A1 allele have altered presynaptic dopamine function in the brain. They also studied the effects of two other DRD2 polymorphisms, C957 T and -141C Ins/Del, which have been suggested to affect D2 receptor levels in brain. The relation between the Taq IA RFLP, C957 T and-141C Ins/Del polymorphisms and striatal dopamine synthesis in 33 healthy Finnish volunteers was studied using PET scans and [18F] fluorodopa ([18F] FDOPA), a radiolabeled analog of the dopamine precursor L-DOPA. Heterozygous carriers of the A1 allele (A1 /A2; 10 subjects) had significantly higher (18%) [18F] FDOPA uptake in the putamen than subjects without the A1 allele (A2/A2; 23 subjects). C957 T and-141C Ins/Del polymorphisms did not significantly affect [18F] FDOPA Ki values. These results demonstrated that the A1 allele of the DRD2 gene is associated with increased striatal activity of aromatic L-amino acid decarboxylase, the final enzyme in the biosynthesis of dopamine and the rate-limiting enzyme for trace amine (e.g., beta-phenylethylamine) synthesis. The finding can be explained by lower D2 receptor expression leading to decreased autoreceptor function, and suggests that the dopamine and/or the trace amine synthesis rate is increased in the brains of A1 allele carriers to compensate.

We are proposing that with an increased striatal activity of aromatic L-amino acid decarboxylase, the final enzyme in the biosynthesis of dopamine and the rate-limiting enzyme for trace amine (e.g. beta-phenylethylamine), dopamine synthesis should occur with a more natural and less powerful agonistic compound relative to L-dopa. This would support the use of NAAT, a precursor amino acid and enkephalinase therapy, as a indirect dopamine agonist. It is postulated that a lower dopamine quanta release at presynaptic neurons in the NAc should result in an up-regulation of post-synaptic D2 receptors in A1 carriers, which will ultimately result in a reduction of craving behavior.

Finally the preliminary findings in United States using qEGG and China using fMRI regarding the effects of oral NAAT in addicts on activation of brain reward circuitry provides potentially important results. It seems from this preliminary data, utilizing an fMRI 2X2 design at resting state, NAAT in comparison to placebo shows activation of the caudate brain region and potentially a smoothing out of heroin-induced putamen abnormal connectivity. If further confirmed in the ongoing studies in China coupled with the qEEG results showing an increase in alpha and increase in low beta may have important treatment outcomes. Cautiously these results are in progress and must await final analysis.

This is the only known agent in the nutraceutical industrial space that on an acute basis "normalizes" persistent qEEG abnormalities in protracted abstinence in serious psychostimulant abusers. Preliminary analysis from fMRI demonstrates that it may even activate reward pathways deficient in D2 density in the mesolimbic system and along with the proposed Genetic Addiction Risk Score [GARS] panel (Blum et al. 2010b) warrants intensive investigation. Necessary large population studies confirming these results will indeed provide evidence whereby "science meets recovery" (Giordano & Blum 2010).

DOI: 10.1080/02791072.2011.587393

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Thomas J.H. Chen, Ph.D. *; Kenneth Blum, Ph.D.**; Amanda L.C. Chen, Ph D. ***; Abdalla Bowirrat, Ph.D., M.D. ****; William B. Downs, B.Sc. *****; Margret A. Madigan, B.S.N. ******; Roger L. Waite, D.C. *******; John A. Bailey, M.D. ********; Mallory Kerner *********; Swetha Yeldandi, B.Sc. *********; Neil Majmundar *********; John Giordano, M.A.C., Ph.D. (hon) **********; Siohban Morse, M.Sc. ***********; David Miller, Ph.D. ************; Frank Fornari, Ph.D. ************* & Eric R. Braverman, M.D. **************

([dagger]) Conflict of Interest: Kenneth Blum, Roger L. Waite, William B. Downs, Margaret Madigan, own stock in LifeGen, Inc; KB220/Kb220Z/KB220IV and all patents thereof have been exclusively licensed to LifeGen, Inc.,

Please address correspondence and reprint requests to Kenneth Blum, Ph.D., Department of Psychiatry, University of Florida School of Medicine and McKnight Brain Institute, Gainesville, FL; phone: (619) 890 2167, email: drd2gene@aol.com

* Professor, Department of Occupational Safety and Health, Chang Jung Christian University, Taiwan, Republic of China.

** Professor, Department of Psychiatry, University of Florida School of Medicine and Mcknight Brain Institute, Gainesville, FL; Chief Scientific Officer, Department of Nutrigenomics and Personalized Medicine, LifeGen, Inc. San Diego, CA, Scientific Advisor, Department of Holistic Medicine, Holistic Addiction Treatment Center, North Miami Beach, FL; Faculty, Department of Research, National Institute of Holistic Studies, North Miami Beach, FL.

*** Professor, Engineering and Management of Advanced Technology, Chang Jung Christian University, Taiwan, Republic of China.

**** Professor, Clinical Neuroscience & Population Genetics & Department of Neurology, Ziv Medical Center, Safad, Israel.

***** President, CEO and Product Development Scientist, Department of Nutrigenomics and Personalized Medicine, LifeGen, Inc., San Diego, CA.

****** Scientist and Editor, Department of Nutrigenomics, LifeGen, Inc., San Diego, CA.

******* Vice President, Department of Nutigenomics, LifeGen, Inc., San Diego, CA.

******** Professor, Department of Psychiatry, University of Florida School of Medicine and Mcknight Brain Institute, Gainesville, FL.

********* Intern, Department of Clinical Neurology, Path Foundation NY, New York.

********** President and Clinical Director, Department of Holistic Medicine Holistic Addiction Treatment Center, North Miami Beach, FL.

*********** Senior Scientist and Director, Department of Research, National Institute of Holistic Studies, North Miami Beach, FL.

************ Owner, Lifestream Inc., Prescott, AZ.

************* President, Dominion Diagnostics Inc. North Kingstown, RI.

************** Clinical Assistant Professor, Department of Neurosurgery, Weill Cornell College of Medicine, New York; Department of Clinical Neurology, Path Foundation NY, New York.
TABLE 1
Genetic Addiction Risk Score (GARS) Proposed Gene Panel

Gene Significant Comment

ALDH2 ++ P = 5 x [10.sup.-37] With alcoholism and
 alcohol-induced medical
 diseases.
ADH1B ++ P = 2 x [10.sup.-21] With alcoholism and
 alcohol-induced medical
 diseases.
ADH1C ++ P = 4 x [10.sup.-33] With alcoholism and
 alcohol-induce medical
 diseases.
DRD2 + P = 1 x [10.sup.-8] With alcohol and drug abuse.
DRD4 + P = 1 x [10.sup.-2] With alcohol and drug abuse.
SLC6A4 ++ P = 2 x [10.sup.-3] With alcohol, heroin, cocaine,
 methamphetamine dependence.
HTRIB + P = 5 x [10.sup.-1] With alcohol and drug abuse.
HTRI2A + P = 5 x [10.sup.-1] With alcohol and drug abuse.
TPH + P = 2 x [10.sup.-3] With alcohol and drug abuse.
MAOA + P = 9 x [10.sup.-5] With alcohol and drug abuse.
OPRD1 ++ P = 5 x [10.sup.-1] With alcohol and drug abuse.
GABRG2 ++ P = 5 x [10.sup.-4] With alcohol and drug abuse.
GABRA2 + P = 7 x [10.sup.-4] With alcohol and drug abuse.
GABRA6 ++ P = 6 x [10.sup.-4] With alcohol and drug abuse.
COMT + P = 5 x [10.sup.-1] With alcohol and drug abuse in
 Asians.
DAT1 + P = 5 x [10.sup.-1] With alcohol and drug abuse in
 Asians.
CNR1 + P = 5 x [10.sup.-1] With alcohol and drug abuse.
CYP2E1 ++ P = 7 x [10.sup.-2] With alcohol liver disease.
ANKKI ++ P = 5 x [10.sup.-6] With alcohol and drug abuse.

+ Based on US patent #6, 955, 873 B1; ++ No patent. Source: Li et al.
2008; Yang et al. 2011.

TABLE 2
NAAT Imaging Studies

 NAAT
Method IV Addiction No Trial Type

Clinical IV Alcoholics with 600 PBC
 polydrug abusers
 secondary drug choice
qEEG IV Alcohol and opiate 2 NC
qEEG Oral Protracted abstinent 10 TBRPCO
 psycho-stimulant
 addicts
fMRI Oral Protracted heroin addicts 5 DBRPCO

Method Results

Clinical Significant reduction in many RDS
 type behaviors (Pre vs. post NAAT
 administration
qEEG In a 24-year-old single depressed
 alcoholic the baseline EEG analysis
 shows increased widespread theta
 (4-8hz) and increased frontal beta
 (12-25hz) compared to the norm.
 Post EEG analysis shows decreased
 frontal theta (4-8hz) and decreased
 frontal beta (12-15hz) indicating
 improved functioning immediately
 post amino acid intravenous
 treatment. In a 24-year-old heroin
 addict post intravenous amino acid
 treatment decreased widespread
 theta at 4-7hz and at 15-16hz
 indicating improved functioning
qEEG To date in preliminary analysis we
 found that a comparison of the FFT
 absolute power (uVSq) of alpha
 (8-12Hz) demonstrated higher
 activity in the NAATgroup
 compared to the placebo group.
 Similarly observing the FFT
 absolute power (uVSq) of low beta
 (12.0 15hz), the activity is
 considerably larger in the NAAT
 group compared to the placebo
 group.
fMRI The resultant data is only related to the
 resting state and preliminary data
 illustrates that just one dose of
 NAAT post oral amino acid
 treatment induces activation at the
 caudate-putamen -NAc brain
 regions.

Method Comment Source

Clinical Shows significant evidence for Blum et al.
 anti-RDS 2007b
qEEG Shows qEEG abnormalities improve Miller et al.
 with an acute IV dose of NAAT 2010
qEEG There was a consistent effect of NAAT Blum et al.
 on frontal regions when compared 2010a
 to placebo. The p values for group 1
 (NAAT) versus group 2 (placebo)
 for a between-group analysis of
 week 1 and week 2 whereby group
 comparisons utilizing T-tests were
 performed resulted in significant
 differences
fMRI There is also the possibility that these Research in
 data also illustrate a reversal of progress.
 putamen abnormalities following
 heroin abuse.

PBC = Prebaseline control.

NC = No control.

TBRPCO = Triple-blind-randomized-placebo-controlled crossover.

DBRPCO = Double-blind-randomized-placebo-controlled crossover.

TABLE 3
Summary of Recent Clinical Trials Supporting Reward Deficiency
Syndrome

Neuro
Adaptagen
Variant Benefit

KB220 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). 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. Of all the outcomes and
 gene polymorphisms, only the DRD2 gene polymorphism (A1
 allele) had a significant Pearson correlation with days
 of treatment (r = 0.42, p = 0.045).
KB220 Pre and post hoc analysis following customization based
 on DNA profiles of five genes revealed significant
 differences between the starting BMI and the BMI
 following an average of 41 days of KB220 intake (p <
 0.034). Similarly, weight in pounds also showed
 significant reductions (p < 0.047). In fact, 71.4% of
 subjects lost weight with a z score of 2.4 and
 significance value of p < 0.02.
KB220 Experiments performed with DNA-polymorphic customized
 KB220 to treat obesity carriers of the DRd2 A1 allele
 had a two-fold higher compliance in terms of staying on
 KB220 compared to the Drd2 A2 carriers. This is very
 consistent with the literature insisting a better
 treatment compliance with D2 agonist therapy such as
 bromocryptine.
KB220 In this randomized double-blind placebo controlled study
 of 62 alcoholic and polydrug abusers, we utilized skin
 conductance level (SCL) to evaluate stress responses.
 Patients receiving KB220 had a significantly reduced
 stress response as measured by SCL, compared to patients
 receiving the placebo. Two factor ANOVA yielded
 significant differences as a function of Time (p <
 0.001), and Treatment (p < 0.025) as well as a Time-by-
 Treatment interaction (p < 0.01).
KB220-IV We report that the quantitative electroencephalographic
 (qEEG) ofboth 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 one IV dose of KB220-IV. The Z
 scores become statistically significant at +-1.9. The
 findings support that the topographical illustrations
 are statistically significant in the pre to post
 improvement in cortical regulation and in normalization
 of EEG activity across the cortex after one dose of the
 KB220-IV amino acid protocol.
KB220-Z Positive outcomes demonstrated by qEEG imaging in a
 randomized triple-blind placebo controlled crossover
 study involving oral KB220-Z showed an increase of alpha
 and low beta activity in the parietal brain region.
 Using t-statistics, significant differences were
 observed between placebo and KB220-Z; they consistently
 occurred in the frontal regions after week one and then
 again after week two of analyses p = .03). This is the
 first report to demonstrate involvement of the
 prefrontal cortex in the qEEG response to a natural
 putative D2 agonist (KB220-Z) especially in dopamine D2
 A1 allele subjects. Independently we have further
 confirmed this finding in an additional three serious
 psychostimulant addicts undergoing protracted abstinence
 with all carrying the DRD2 A1 allele. Significant qEEG
 differences were found between one dose of placebo
 compared to KB220-Z administration. Once again KB220-Z
 induced positive effects by increasing regulated brain
 waves associated with reduced craving of psychoactive
 substances. The results are indicative of a phase change
 from low amplitude or low power in the brain to a more
 regulated state by increasing an average of 6.169
 microvolts squared across the prefrontal cortical region

Neuro
Adaptagen
Variant Reference Comment

KB220 Blum et al. 2008b The patient population was derived
 from consumers of both KB220 and
 the DNA test. Each obese patient
 in the study responded to a pre
 and post questionnaire
KB220 Blum et al. 2008c Each patient served as his/her own
 control. The patients were obese
 consumers attending a clinic
 called DNA Services of America.
 Each patient willingly purchased
 the obesity DNA test panel and
 responded to a pre and post
 questionnaire.
KB220 Blum et al. 2008d The subjects were a subset of over
 100 participants in an open label
 study in the Netherlands. Each
 subject was administered their own
 customized DND directed formula
 based on genotyping five candidate
 genes.
KB220 Blum, Chen & Chen The present study investigated
 anti-anxiety effects of KB220, a
 2009 dopaminergic activator, in a
 randomized double-blind placebo
 controlled study in alcoholics and
 in polydrug abusers attending an
 inpatient chemical dependency
 program. The results of this study
 suggest that the KB220 may improve
 treatment response in an inpatient
 treatment setting by reducing
 stress related behaviors and
 warrants further investigation.
KB220-IV Miller et al. 2010 Two case reports showing acute IV
 administration normalizes
 electrical activity of the
 orbital-frontal/prefrontal
 cortical regions of the brain.
 This is very important in terms of
 craving behavior in general
 because this dysregulation affects
 the cingulated gyrus, which has
 been adequately linked to the
 mesolimbic reward system and
 craving behavior.
KB220-Z Blumetal. 2010a This is the only known agent in the
 nutraceutical industrial space
 that on an acute basis
 "normalizes" persistent qEEG in
 protracted abstinence in serious
 psychostimulant abusers and as
 such reduces craving behavior.

TABLE 4
Neuroadaptagen Amino Acid (NAAT) Variants

Neuroadaptagen Amino Acid (NAAT) Variants

L-Phenylalanine
L-Tyrosine
L-Tryptophan
5-Hydroxytryptophane
L-Glutamine (a serotonin concentrating substance)
Chromium (an enkephalinase inhibitor)
D-Phenylalanine (neurotransmitter synthesis promoter)
Vitamin B6
Methionine and Leucine
Rhoiola rosea
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Author:Chen, Thomas J.H.; Blum, Kenneth; Chen, Amanda L.C.; Bowirrat, Abdalla; Downs, William B.; Madigan,
Publication:Journal of Psychoactive Drugs
Article Type:Report
Geographic Code:1USA
Date:Jun 1, 2011
Words:14565
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