LG839: Anti-obesity effects and polymorphic gene correlates of reward deficiency syndrome. Advances in Therapy

Weill Cornell Medical College Department of Neurosurgery New York New York USA
Advances in Therapy (Impact Factor: 2.44). 09/2008; 25(9):894-913. DOI: 10.1007/s12325-008-0093-z
Source: PubMed

ABSTRACT IntroductionThis study systematically assessed the weight management effects of a novel experimental DNA-customized nutraceutical, LG839
(LifeGen®, Inc., La Jolla, CA, USA).

MethodsA total of 1058 subjects who participated in the overall D.I.E.T. study were genotyped and administered an LG839 variant based
on polymorphic outcomes. A subset of 27 self-identified obese subjects of Dutch descent, having the same DNA pattern of four
out of the five candidate genes tested (chi-square analysis) as the entire data set, was subsequently evaluated. Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed.

ResultsSignificant 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-γ2, 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 on treatment (r=0.42, P=0.045).

ConclusionIf these results are confirmed in additional rigorous, controlled studies, we carefully suggest that DNA-directed targeting
of certain regulator genes, along with customized nutraceutical intervention, provides a unique framework and strategic modality
to combat obesity.

Download full-text


Available from: Bernard William Downs, Sep 01, 2015
  • Source
    • "Since that time there have been no less than 3738 (Pubmed-6-23-14) peer reviewed articles on many peripheral and central nervous system (CNS) behaviors and physiological processes. Understandably addiction or even the broader term RDS involves very complex gene × environment interaction and one cannot expect that a single gene like the DRD2 gene would have a powerful effect by itself, however, albeit many negative findings, there is still a plethora of evidence for the role of the DRD2 gene polymorphisms and a number (small sample of studies represented herein) of addictive and other reward dependent behaviors including: alcohol dependence (Pato et al., 1993; Ponce et al., 2003; Munafò et al., 2007; Smith et al., 2008; Pinto et al., 2009; Grzywacz et al., 2012; Wang et al., 2013); drug dependence (Li et al., 2004; Xu et al., 2004; Young et al., 2004; Barratt et al., 2006; Li et al., 2006; Hou and Li, 2009; Chen et al., 2011a,b; Al-Eitan et al., 2012; Jacobs et al., 2013; Lee et al., 2013; Ohmoto et al., 2013; Sullivan et al., 2013; Suraj Singh et al., 2013; Vereczkei et al., 2013; Wang et al., 2013; Clarke et al., 2014; Roussotte et al., 2014; Schuck et al., 2014); mood disorders (Vaske et al., 2009; Huertas et al., 2010; Zhu et al., 2011; Zou et al., 2012; Hettinger et al., 2012; Jutras-Aswad et al., 2012; Tsuchimine et al., 2012; Whitmer and Gotlib, 2012; Zai et al., 2012; Peciña et al., 2013; Zhang et al., 2014); rearing behaviors (Mills-Koonce et al., 2007; Bakermans-Kranenburg and van Ijzendoorn, 2011; Beaver and Belsky, 2012; Masarik et al., 2014); obesity (Spangler et al., 2004; Fang et al., 2005; Huang et al., 2005; Epstein et al., 2007; Nisoli et al., 2007; Barnard et al., 2008; Blum et al., 2008; Eny et al., 2009; Epstein et al., 2010; Mathes et al., 2010; Stice et al., 2010; van Strien et al., 2010; Jabłoński, 2011; Anitha et al., 2012; Chen et al., 2012; Winkler et al., 2012; Ariza et al., 2013; Carpenter et al., 2013; Cameron et al., 2013; Hess et al., 2013; Alsiö et al., 2014); Anorexia Nervosa (Bergen et al., 2005); motivation (Trifilieff et al., 2013); brain metabolism (Noble et al., 1997); ADHD (Gold et al., 2014), and pathological gambling (Gyollai et al., 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Obesity and many well described eating disorders are accurately considered a global epidemic. The consequences of Reward Deficiency Syndrome, a genetic and epigenetic phenomena that involves the interactions of powerful neurotransmitters, are impairments of brain reward circuitry, hypodopaminergic function and abnormal craving behavior. Numerous sound neurochemical and genetic studies provide strong evidence that food addiction is similar to psychoactive drug addiction. Important facts which could translate to potential therapeutic targets espoused in this review include: 1) brain dopamine (DA) production and use is stimulated by consumption of alcohol in large quantities or carbohydrates bingeing; 2) in the mesolimbic system the enkephalinergic neurons are in close proximity, to glucose receptors; 3) highly concentrated glucose activates the calcium channel to stimulate dopamine release from P12 cells; 4) blood glucose and cerebrospinal fluid concentrations of homovanillic acid, the dopamine metabolite, are significantly correlated and 5) 2-deoxyglucose the glucose analogue, in pharmacological doses associates with enhanced dopamine turnover and causes acute glucoprivation. Evidence from animal studies and human fMRI support the hypothesis that multiple, but similar brain circuits are disrupted in obesity and drug dependence and DA-modulated reward circuits are involved in pathologic eating behaviors. Treatment for addiction to glucose and drugs alike, based on a consensus of neuroscience research, should incorporate dopamine agonist therapy, in contrast to current theories and practices that use dopamine antagonists. Until now, powerful dopamine-D2 agonists have failed clinically, due to chronic down regulation of D2 receptors instead, consideration of novel less powerful D2 agonists that up-regulate D2 receptors seems prudent. We encourage new strategies targeted at improving DA function in the treatment and prevention of obesity a subtype of reward deficiency.
    Frontiers in Psychology 09/2014; 5:919. DOI:10.3389/fpsyg.2014.00919 · 2.80 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND AND HYPOTHESIS: Based on neurochemical and genetic evidence, we suggest that both prevention and treatment of multiple addictions, such as dependence to alcohol, nicotine and glucose, should involve a biphasic approach. Thus, acute treatment should consist of preferential blocking of postsynaptic Nucleus Accumbens (NAc) dopamine receptors (D1-D5), whereas long term activation of the mesolimbic dopaminergic system should involve activation and/or release of Dopamine (DA) at the NAc site. Failure to do so will result in abnormal mood, behavior and potential suicide ideation. Individuals possessing a paucity of serotonergic and/or dopaminergic receptors, and an increased rate of synaptic DA catabolism due to high catabolic genotype of the COMT gene, are predisposed to self-medicating any substance or behavior that will activate DA release, including alcohol, opiates, psychostimulants, nicotine, gambling, sex, and even excessive internet gaming. Acute utilization of these substances and/or stimulatory behaviors induces a feeling of well being. Unfortunately, sustained and prolonged abuse leads to a toxic" pseudo feeling" of well being resulting in tolerance and disease or discomfort. Thus, a reduced number of DA receptors, due to carrying the DRD2 A1 allelic genotype, results in excessive craving behavior; whereas a normal or sufficient amount of DA receptors results in low craving behavior. In terms of preventing substance abuse, one goal would be to induce a proliferation of DA D2 receptors in genetically prone individuals. While in vivo experiments using a typical D2 receptor agonist induce down regulation, experiments in vitro have shown that constant stimulation of the DA receptor system via a known D2 agonist results in significant proliferation of D2 receptors in spite of genetic antecedents. In essence, D2 receptor stimulation signals negative feedback mechanisms in the mesolimbic system to induce mRNA expression causing proliferation of D2 receptors. PROPOSAL AND CONCLUSION: The authors propose that D2 receptor stimulation can be accomplished via the use of Synapatmine, a natural but therapeutic nutraceutical formulation that potentially induces DA release, causing the same induction of D2-directed mRNA and thus proliferation of D2 receptors in the human. This proliferation of D2 receptors in turn will induce the attenuation of craving behavior. In fact as mentioned earlier, this model has been proven in research showing DNA-directed compensatory overexpression (a form of gene therapy) of the DRD2 receptors, resulting in a significant reduction in alcohol craving behavior in alcohol preferring rodents. Utilizing natural dopaminergic repletion therapy to promote long term dopaminergic activation will ultimately lead to a common, safe and effective modality to treat Reward Deficiency Syndrome (RDS) behaviors including Substance Use Disorders (SUD), Attention Deficit Hyperactivity Disorder (ADHD), Obesity and other reward deficient aberrant behaviors. This concept is further supported by the more comprehensive understanding of the role of dopamine in the NAc as a "wanting" messenger in the meso-limbic DA system.
    Theoretical Biology and Medical Modelling 12/2008; 5:24. DOI:10.1186/1742-4682-5-24 · 1.27 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Since 1990, researchers have proposed that genetic variants of dopaminergic genes and other "reward genes" are important common determinants of Reward Deficiency Syndrome (RDS). RDS refers to the breakdown of a cascade of neurotransmitters in the brain in which one reaction triggers another — the reward cascade — and resultant aberrant conduct. Association studies have amassed strong evidence implicating the D (2) dopamine receptor (DRD2) gene in harmful conditions such as alcoholism, and the DRD2 gene also has been found to be involved in other substance use disorders including cocaine, nicotine, and opioid dependence, as well as obesity. 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. 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 Synaptamine Complex [KB220] had a significantly reduced stress response as measured by SCL, compared to patients receiving 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). The results of this study suggest that the Synaptamine Complex™ [KB220] may improve treatment response in an in-patient treatment setting by reducing stress related behaviors and warrants further investigation.
Show more