Narcotic antagonists in drug dependence: pilot study showing enhancement of compliance with SYN-10, amino-acid precursors and enkephalinase inhibition therapy

Chen, Thomas J H; Blum, Kenneth; Payte, J. Thomas; Schoolfield, John; Hopper, David L.; Stanford, Mathew; Braverman, Eric R.

doi:10.1016/j.mehy.2004.02.051

Cited by 48 publications

(30 citation statements)

References 32 publications

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“…53 The role of dopaminergic receptors as key in regulating a variety of RDS behaviors including cocaine and food has been further supported by work from Volkow’s group. 54 Since 1978 we have been developing the concept of nutritional genetics with special emphasis on an amino-acid based enkephalinase approach to the treatment of alcohol [55], 55 cocaine, 56 opiates, 57 glucose, 58 and other addictions 59 pointing out the importance of dietary supplementation and the addictive brain which has served a basis for the current experiment.…”

Section: Discusionmentioning

confidence: 99%

rsfMRIeffects of KB220Z™ on neural pathways in reward circuitry of abstinent genotyped heroin addicts

Blum

Liu

Wang

et al. 2014

Postgraduate Medicine

Self Cite

123

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Recently 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, also associated with lower activation to cues in occipital cortex and cerebellum in a recent PET study from Volkow’s group. Therefore, treatment strategies, like dopamine agonist therapy, that might conserve dopamine function may be an interesting approach to relapse prevention in psychoactive drug and behavioral addictions. To this aim, we evaluated the effect of KB220Z™ on reward circuitry of ten heroin addicts undergoing protracted abstinence, an average 16.9 months. In a randomized placebo-controlled crossover study of KB220Z™ five subjects completed a triple blinded–experiment in which the subject, the person administering the treatment and the person evaluating the response to treatment were blinded as to which treatment any particular subject was receiving. In addition, nine subjects total were genotyped utilizing the GARSRX™ test. We preliminarily report that KB220Z ™ induced an increase in BOLD activation in caudate-accumbens-dopaminergic pathways compared to placebo following one-hour acute administration. Furthermore, KB220Z™ also reduced resting state activity in the putamen of abstinent heroin addicts. In the second phase of this pilot study of all ten abstinent heroin-dependent subjects, three brain regions of interest (ROIs) we observed to be significantly activated from resting state by KB220Z compared to placebo (P < 0.05). 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. These results and other qEEG study results suggest a putative anti-craving/anti-relapse role for KB220Z in addiction by direct or indirect dopaminergic interaction. Due to small sample size, we caution definitive interpretation of these preliminary results and confirmation with additional research and ongoing rodent and human studies of KB220Z, is required.

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Section: Discusionmentioning

confidence: 99%

rsfMRIeffects of KB220Z™ on neural pathways in reward circuitry of abstinent genotyped heroin addicts

Blum

Liu

Wang

et al. 2014

Postgraduate Medicine

Self Cite

123

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“…It is noteworthy that addicts in withdrawal are known to overeat sugar perhaps as a substitute for the actions of opiates on the brain. Their drive for sugar is such that it can lead to obesity and glucose dysregulation [161–163]. Hence, targeting anti-craving treatments used in opiate addiction may prove beneficial in treating binge-eating (e.g., with buprenorphin [164], buprenorphin/naloxone [165], D-phenylalanine/L-amino-acids/naloxone [163]).…”

Section: Selected Neurotransmitter Systems Implicated In Binge Eatingmentioning

confidence: 99%

“…Their drive for sugar is such that it can lead to obesity and glucose dysregulation [161–163]. Hence, targeting anti-craving treatments used in opiate addiction may prove beneficial in treating binge-eating (e.g., with buprenorphin [164], buprenorphin/naloxone [165], D-phenylalanine/L-amino-acids/naloxone [163]). The identification of gene markers that are common between opiate addiction and binge eating (rather than obesity) may also accelerate treatment progress.…”

Section: Selected Neurotransmitter Systems Implicated In Binge Eatingmentioning

confidence: 99%

Feeding and reward: Perspectives from three rat models of binge eating

Corwin

Avena

Boggiano

2011

Physiology & Behavior

260

187

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Research has focused on understanding how overeating can affect brain reward mechanisms and subsequent behaviors, both preclinically and in clinical research settings. This work is partly driven by the need to uncover the etiology and possible treatments for the ongoing obesity epidemic. However, overeating, or non-homeostatic feeding behavior, can occur independent of obesity. Isolating the variable of overeating from the consequence of increased body weight is of great utility, as it is well known that increased body weight or obesity can impart its own deleterious effects on physiology, neural processes, and behavior. In this review, we present data from three selected animal models of normal-weight non-homeostatic feeding behavior that have been significantly influenced by Bart Hoebel’s 40+-yr career studying motivation, feeding, reinforcement, and the neural mechanisms that participate in the regulation of these processes. First, a model of sugar bingeing is described (Avena/Hoebel), in which animals with repeated, intermittent access to a sugar solution develop behaviors and brain changes that are similar to the effects of some drugs of abuse, serving as the first animal model of food addiction. Second, another model is described (Boggiano) in which a history of dieting and stress can perpetuate further binge eating of palatable and non-palatable food. In addition, a model (Boggiano) is described that allows animals to be classified as having a binge-prone vs. binge-resistant phenotype. Lastly, a limited access model is described (Corwin) in which non-food deprived rats with sporadic limited access to a high-fat food develop binge-type behaviors. These models are considered within the context of their effects on brain reward systems, including dopamine, the opioids, cholinergic systems, serotonin, and GABA. Collectively, the data derived from the use of these models clearly show that behavioral and neuronal consequences of bingeing on a palatable food, even when at a normal body weight, are different from those that result from simply consuming the palatable food in a non-binge manner. These findings may be important in understanding how overeating can influence behavior and brain chemistry.

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“…A summary of combining this data suggests that utilization of a putative D 2 agonist could ultimately lead to a significant reduction of relapse rates of only 20.25% [see Table 1]. Other studies also utilizing Synaptamine variants result in positive anti-drug seeking behavior in both in-patient [240] and out-patient [241] treatment.…”

Section: “Deprivation-amplification Relapse Therapy” [Dart]mentioning

confidence: 99%

Neurogenetics of Dopaminergic Receptor Supersensitivity in Activation of Brain Reward Circuitry and Relapse: Proposing “Deprivation-Amplification Relapse Therapy” (DART)

Blum

Chen

Downs³

et al. 2009

Postgraduate Medicine

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Background and Hypothesis It is well known that after prolonged abstinence, individuals who imbibe or use their drug of choice experience a powerful euphoria that precipitates serious relapse. While a biological explanation for this conundrum has remained elusive, we hypothesize that this clinically observed “super sensitivity” might be tied to genetic dopaminergic polymorphisms. Another therapeutic conundrum relates to the paradoxical finding that the dopaminergic agonist bromocriptine induces stronger activation of brain reward circuitry in individuals who carry the DRD2 A1 allele compared to DRD2 A2 allele carriers. Based upon the fact that carriers of the A1 allele relative to the A2 allele of the DRD2 gene have significantly lower D2 receptor density, a reduced sensitivity to dopamine agonist activity would be expected in the former. Thus, it is perplexing that with low D2 density there is an increase in reward sensitivity with the dopamine agonist bromocriptine. Moreover, under chronic or long-term therapy, the potential proliferation of D2 receptors with bromocriptine has been shown in vitro. This seems to lead to a positive outcome and significantly better treatment compliance only in A1 carriers. Proposal and Conclusion We propose that low D2 receptor density and polymorphisms of the D2 gene are associated with risk for relapse of substance abuse including alcohol dependence, heroin craving, cocaine dependence, methamphetamine abuse, nicotine sensitization, and glucose craving. With this in mind, we suggest a putative physiological mechanism that may help to explain the enhanced sensitivity following intense acute dopaminergic D2 receptor activation: “denervation supersensitivity.” Thus, the administration of dopamine D2 agonists would target D2 sensitization and attenuate relapse, especially in D2 receptor A1 allele carriers. This hypothesized mechanism is supported by clinical trials utilizing the amino-acid neurotransmitter precursors, enkephalinase and catechol-O-methyl-transferase (COMT) enzyme inhibition, which have resulted in attenuated relapse rates in Reward Deficiency Syndrome (RDS) probands. Future warranted translational research with positive outcome showing prevented or lower relapse in RDS will ultimately support the proposed concept, which we term “Deprivation-Amplification Relapse Therapy (DART).”

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Narcotic antagonists in drug dependence: pilot study showing enhancement of compliance with SYN-10, amino-acid precursors and enkephalinase inhibition therapy

Cited by 48 publications

References 32 publications

rsfMRIeffects of KB220Z™ on neural pathways in reward circuitry of abstinent genotyped heroin addicts

rsfMRIeffects of KB220Z™ on neural pathways in reward circuitry of abstinent genotyped heroin addicts

Feeding and reward: Perspectives from three rat models of binge eating

Neurogenetics of Dopaminergic Receptor Supersensitivity in Activation of Brain Reward Circuitry and Relapse: Proposing “Deprivation-Amplification Relapse Therapy” (DART)

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