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Daxitrol: A Novel Approach for Controlling Cravings David Marc, B.Sc.a, & Kelly Olson Ph.Da. a NeuroScience, Inc., 373 280th St., Osceola, WI 54020, United States [email protected] ABSTRACT
Cravings are defined as an intense drive or desire directed towards food, drugs, gambling, and other stimuli. The pleasure/reward and motivational pathways associated with cravings involve multiple neurotransmitters including dopamine, glutamate, serotonin, acetylcholine, and various peptides. These neurotransmitters also serve as therapeutic targets to modulate the pleasure/reward pathway. Daxitrol is a novel product that contains L-3,4-dihydroxyphenylalanine (L-DOPA), epigallocatechin gallate (EGCG), N-acetylcysteine (NAC), 5-hydroxytryptophan (5- HTP), L-phenylalanine, forskolin, and huperzine A (HupA) to manage cravings and enhance self-control. This overview will present the neurological pathways that underlie cravings and propose the use of Daxitrol to ameliorate cravings. Information will be provided that discusses how Daxitrol targets dopamine, glutamate, serotonin, acetylcholine, and the peptide cholecystokinin (CCK) to help decrease cravings and INTRODUCTION
1989). Although cravings decrease with the intake of sweets, the Cravings are defined as an intense drive or desire for a likelihood of weight issues increases due to their high caloric value variety of stimuli (Pelchat, 2002). Commonly, cravings are directed towards foods or drugs and have been reported to occur in Whether cravings are directed towards foods or drugs, approximately 52–97% of individuals (Gendall et al., 1997; it is related to the lack of impulse control (Pelchat, 2002). Christensen & Pettijohn, 2001). Cravings can also be directed Similarly, impulsivity is observed with cravings toward other towards behaviors that elicit a desire for intangible stimuli as stimuli such as gambling (Iancu et al., 2008). Because cravings are observed in gambling (Tavares et al., 2005). Interestingly, the related to the pursuit of pleasure and reward and the impulsive same biochemical pathways and neurological circuits are need for a specific stimulus, cravings share similar biological implicated in cravings for food, drugs, and gambling (Pelchat, systems independent of the stimulus being craved (Pelchat, 2002). 2002). Daxitrol is a product that targets these neurological circuits Therefore, a product, such as Daxitrol, that targets the biochemical by supporting specific neurotransmitters involved in the pathways involved with pleasure, reward, and impulsivity may pleasure/reward pathway and therefore can decrease cravings and reduce cravings for a variety of stimuli. Although the biochemical mechanisms of cravings are Food cravings are of interest because of their not fully understood, research strongly suggests the involvement of overwhelming prevalence and the significant impact on weight and dopaminergic brain nuclei in regulating pleasure and reward health. However, there is an evolutionary concept that suggests the (Christensen & Pettijohn, 2001; Heinz et al., 2009). In addition, purpose of food cravings is to promote greater dietary variety. research supports the involvement of other biochemical mediators, Evidence to support this concept has shown that adults who such as serotonin, glutamate, acetylcholine, and various peptides in consumed a single food diet experienced increased food cravings behaviors related to cravings (Heinz et al., 2009). Novel strategies as compared to a baseline diet with greater diversity (Pelchat & are being developed to control cravings by targeting these specific Schaefer, 2000). However, food cravings tend to be directed biochemical pathways. This overview introduces and explains the towards highly-palatable, calorie-dense foods such as chocolate, neurological pathways involved in cravings and provide evidence candy, and pizza (Weingarten & Elston, 1991). Consequently, for the use of the novel product, Daxitrol, to manage these cravings can contribute to weight gain (Krebs-Smith et al., 1987; Drug and food cravings involve activation of similar THE BIOLOGY OF CRAVINGS
biochemical pathways leading to behaviors related to an impulsive Various neurological systems contribute to the drive to consume a particular substance. Interestingly, programs to behavioral drive for pleasure and reward that can lead to the onset reduce substance use often utilize sweets as a means to reduce drug of cravings. Of primary focus are the neurotransmitters dopamine, cravings (Pelchat, 2002). The ingestion of sweets has shown to glutamate, acetylcholine, and serotonin as they have been shown to reduce cravings for opiates, alcohol, and cigarettes (Morabia et al., be involved in these processes (Ciccocioppo, 1999; Clay et al., *These statements have not been evaluated by the Food and Drug Administration.
This product is not intended to diagnose, treat, cure, or prevent any disease.
2008). In addition, a peptide called cholecystokinin (CCK) can for intracellular glutamate, which serves as the primary source of signal satiety, or the feeling of “fullness”, and can decrease drug extracellular glutamate in the NAc (Knackstedt et al., 2009). intake by altering specific actions in the central nervous system Extracellular glutamate differs from synaptic glutamate by acting (CNS) (Dockray, 2009; Watkins et al., 1985). primarily on autoreceptors found on the presynaptic glutamate Dopamine is important in reward and motivation. The neuron, whereas, synaptic glutamate primarily acts on receptors dopaminergic brain regions that are associated with cravings found on the postsynaptic neuron. The normal physiological role of include the nucleus accumbens (NAc), ventral tegmental area extracellular glutamate in the NAc is part of a negative feedback (VTA), and neostriatum (Clay et al., 2008). A variety of drugs loop to prevent excessive glutamate release and reduce synaptic such as opiods, alcohol, cocaine, and amphetamines elicit intense glutamate levels (Figure 1; Moran et al., 2005). Research has dopaminergic signals in the brain that induce a pleasurable demonstrated that overtime drug use can decrease xc- transport behavioral response (Di & Imperato, 1988). Likewise, gambling function resulting in decreased extracellular glutamate and can increase the activity of the same dopaminergic pathways increased synaptic glutamate release (LaRowe et al, 2006). (Iancu et al., 2008). Food is another powerful stimulator of Decreased activity of the xc- transport system contributes to dopaminergic reward regions in the brain (Epstein & Leddy, increased cravings and perpetuation of drug use (LaRowe et al., 2006). Upon initial exposure to a rewarding stimulus, there is an 2006; Moran et al., 2005). Decreased xc- transport function has increase in dopamine signaling from the VTA to the NAc which also been observed in gambling (Grant et al., 2007) and nail-biting can result in a pleasurable response (Roberts & Koob, 1997). In (Berk et al., 2009) as well as other craving-associated behaviors. addition, the NAc has dense acetylcholine projections that can New strategies which minimize alterations in the xc- transport mediate dopamine release and enhance the reinforcing effects system and decrease cravings are currently in development following the ingestion of foods and drugs (Hikida et al, 2003). In fact, research suggests that increases in brain acetylcholine can Figure 1.
prevent reward seeking behaviors and cravings for food and drugs Recent evidence has suggested that overeating may be a compensatory action in response to a reward deficiency, resulting from hypoactive dopaminergic activity in the brain (Reinholz et al., 2008). Various conditions such as genetic predisposition or downregulation due to preceding dopaminergic overstimulation can lead to deficient dopaminergic stores (Reinholz et al., 2008). Consequently, dopaminergic support may prevent compensatory Dopamine's role in motivation is mediated by The xc- transport system exchanges intracellular glutamate for learned/associative processes in the brain by which exposure to extracellular cystine. Extracellular glutamate can bind to environmental cues can induce a craving. To explain further, drugs presynaptic group II metabotropic autoreceptors (mGluR2/3), which inhibits synaptic glutamate signaling. and foods increase dopamine activity in the NAc which enhances glutamatergic signaling to the prefrontal cortex thereby creating an While dopamine is part of the reward process that association between the environment and the stimuli's pleasurable triggers cravings, serotonin determines the level of motivation to action (Goldstein & Volkow, 2002). Upon later exposure to the satisfy the craving. Specifically, studies have reported that environmental cues, glutamate signals from the prefrontal cortex serotonin depletion can contribute to poor impulse control. project to the NAc to determine the behaviors necessary to obtain Animals that are depleted of serotonin have increased preference the rewarding stimuli (Volkow et al., 2002). The motivation to for a small immediate reward over a larger delayed reward (Bizot seek and obtain these rewarding stimuli results in the manifestation of cravings (Goldstein & Volkow, 2002). The dopamine- and serotonin-based model has been The glutamate signaling that promotes compulsive and proposed as a two-stage process that triggers cravings urge-driven behaviors is regulated by a cystine/glutamate (Ciccocioppo, 1999). In the first stage, dopamine is released as part antiporter, also known as the xc- transport system (Knackstedt et of the learned processes that associate a stimulus (i.e., food, drugs, al., 2009). The xc- transport system exchanges extracellular cystine *These statements have not been evaluated by the Food and Drug Administration.
This product is not intended to diagnose, treat, cure, or prevent any disease. Individual results may vary.
or gambling) with a pleasurable response and triggers the desire to ingredient found in Daxitrol will be described in the subsequent repeat the stimulus, thereby creating cravings. However, adequate section to highlight how each ingredient can decrease cravings. levels of serotonin are able to control the inclination to satisfy the craving (Ciccocioppo, 1999; Weiss et al., 2001). In the second A CLOSER LOOK AT DAXITROL FOR CRAVINGS
stage of the process, continued use of the stimulus results in a Daxitrol is a dietary supplement that contains L-3,4- depletion of serotonin and an inability to control or put-off the desire for the stimulus (Ciccocioppo, 1999). Interestingly, many (EGCG), N-acetylcysteine (NAC), 5-hydroxytryptophan (5-HTP), cravings are often associated with mood issues which can also be L-phenylalanine, forskolin, and huperzine A (HupA) (Table 1). triggered by serotonin deficiencies (Young & Wohl, 2009; The following overview will present how the biological Nakama et al., 2008; Quello et al., 2005; Parker & Crawford, mechanisms of each ingredient found in Daxitrol can help to 2007). As such, support programs designed to minimize the neurotransmitter impediments that result in cravings can also have L-3,4-dihydroxyphenylalanine (L-DOPA) is an amino acid precursor to the catecholamines dopamine, norepinephrine, An emerging area of research is now examining the role and epinephrine (Mena et al., 2009). Low dopamine has been of peptides in food and drug cravings. Many peptides, such as associated with cravings to foods and drugs (Reinholz et al., 2008). gastrin, CCK, secretin, and motilin, are found in the Food consumption and substance use compensate for the gastrointestinal system and can act as neuromodulators that send hypoactive dopaminergic activity and reward deficiency (Reinholz hunger or satiety signals to the brain (Dockray, 2009). These et al., 2008). Ingredients that increase dopamine (Balcioglu & peptides transmit satiety signals through cholinergic stimulation of Wurtman, 1998), such as the L-DOPA found in Daxitrol, may the vagus nerve to relay information from the gastrointestinal prevent a reward deficiency and therefore decrease food and drug system to the brain (Bodenlos et al., 2007a; Bodenlos et al., cravings (Reinholz et al., 2008; Palhagen et al., 2005). 2007b). Extensive research has focused on the peptide CCK and its Epigallocatechin gallate (EGCG) acts as the primary role in controlling food intake and cravings (Crespi et al., 2000; polyphenolic catechin agent in green tea which is responsible for Hirschberg et al., 2004). Interestingly, CCK is found not only in many of green tea’s health benefits (Nagle et al., 2006). EGCG has the gastrointestinal system but also in the brain to further regulate antioxidant properties, promotes healthy cardiovascular function, hunger or satiety signals (Beinfeld et al., 2002). Research has and limits tissue damage following prolonged immune system shown that cocaine and other drugs can lead to decreased hunger activation (Nagle et al., 2006). Energy expenditure can also be and food intake by increasing CCK activity in the brain (Abraham stimulated through the thermogenic effects of EGCG (Hursel et al., et al., 2009, Maletinska et al., 2008). In addition, research has 2009). The thermogenic property of EGCG is attributed to its demonstrated that brain CCK is co-released with dopamine in the ability to inhibit catechol O-methyltransferase (COMT), thereby, NAc where CCK may be associated with pleasure and reward increasing the levels of dopamine and norepinephrine and cyclic responses (Beinfeld et al., 2002). Novel strategies are in adenosine monophosphate (cAMP) (Hursel et al., 2009). Daxitrol development to support CCK to reduce hunger and support the contains EGCG to support catecholamine levels and decrease pleasure reward pathways (Ballinger & Clark, 1994; Dockray, cravings (Sinha et al., 2003), and may aid in weight management by enhancing thermogenesis (Hursel & Westerterp-Plantenga, Cravings can occur via the actions of several biological pathways. Dopamine mediates the pleasure and rewarding N-acetylcysteine is a known precursor for cysteine responses of stimuli whereas serotonin mediates the motivation which is necessary for the synthesis of glutathione, a powerful and impulsive drive to seek-out the stimuli. Acetylcholine antioxidant (Dilger & Baker, 2007; Diniz et al., 2006). However, enhances the dopamine activity that supports pleasure and reward. researchers have also discovered that n-acetylcysteine possesses Glutamate alterations can contribute to impulse behaviors and the ability to decrease drug cravings through alterations of the xc- cravings. Finally, CCK and acetylcholine can also contribute to transport system (LaRowe et al., 2006; Moran et al., 2005). As the intake of a substance by altering hunger and satiety signals. described above, prolonged drug use can decrease xc- transport Overall, Daxitrol is a novel dietary supplement that has been function and lead to elevated synaptic glutamate levels that developed to specifically support these pathways to help decrease contribute to increased cravings (Knackstedt et al., 2009; Moran et the prevalence of cravings. The biological actions of each al., 2005). Oral delivery of n-acetylcysteine can reestablish normal *These statements have not been evaluated by the Food and Drug Administration.
This product is not intended to diagnose, treat, cure, or prevent any disease. Individual results may vary.
xc- transport function and thereby decrease reward-seeking important in many biological processes (Henderson et al., 2005). behavior (LaRowe et al., 2006). Altered xc- transport function is Forskolin has been found to support neuronal catecholamine further implicated in gambling (Grant et al., 2007) and nail-biting activity by increasing the cAMP-accumulating properties (Berk et al., 2009) whereby n-acetylcysteine has been reported to following the activation of catecholamine receptors (Hoffstedt et attenuate these behaviors. N-acetylcysteine is included in Daxitrol al., 2001; Lang et al., 2003). Additionally, forskolin has been to control synaptic glutamate levels and decrease impulsivity and studied extensively for its weight management properties. Fat cells utilize cAMP to breakdown stored fats, regulate the body’s Daxitrol also contains 5-HTP, an amino acid precursor thermogenic response to foods, and increase the body’s metabolic to the monoamine neurotransmitter serotonin. Animal studies have rate (Henderson et al., 2005). Forskolin can support weight reported that 5-HTP reduces food intake (Amer et al., 2004) and management by increasing cAMP which leads to the activation of decreases impulsivity (Ho et al., 1998). 5-HTP is thought to protein kinase A which then activates the production of hormone- modulate these behaviors by increasing the level of serotonin in the sensitive lipase (HSL) (Godard et al., 2005). HSL is the rate- brain and periphery (Ho et al., 1998). Additionally, human studies limiting step in the breakdown of triacylglycerol molecules, have examined the use of 5-HTP and decreased cravings. A short thereby freeing fatty acids for energy (Lafontan & Langin, 2009). term six-week study showed that 5-HTP can reduce food intake in Therefore, forskolin has actions that can promote favorable overweight individuals regardless of dietary restriction (Cangiano changes in body composition (Godard et al., 2005). The inclusion et al., 1992). Similarly, a two-week study of overweight of forskolin in Daxitrol could support dopamine, norepinephrine, individuals reported reduced food intake following 5-HTP and epinephrine activity to control cravings and assist in weight administration compared to placebo (Cangiano et al., 1998). Interestingly, this study also provided evidence that 5-HTP is able Lastly, Daxitrol contains huperzine A (HupA), which is to suppress carbohydrate and fat intake (Cangiano et al., 1998). isolated from the Chinese herb Huperzia serrata. HupA is a potent, 5-HTP can also decrease cravings associated with drug- highly specific, and reversible acetylcholinesterase (AChE) use. A study in rats showed that 5-HTP can decrease the inhibitor (Tang et al., 1989). AChE exists in multiple forms and consumption of alcohol while increasing alcohol avoidance (Zabik acts as the primary enzyme that breaks down acetylcholine et al., 1994). Another study revealed that 5-HTP reduced the desire (Brimijoin, 1983). HupA appears to preferentially inhibit the for cocaine following cocaine withdrawal (Harris et al., 2001). tetrameric G4 form of the acetylcholinesterase enzyme, which is Overall, serotonin supporting agents, such as 5-HTP, can be primarily localized in the central nervous system (Zhao & Tang, helpful for impulse control and limit the use of craved stimuli. 2002). Therefore, HupA selectively increases acetylcholine in the Daxitrol contains 5-HTP to increase self-control, thereby brain (Vigny et al., 1979; Grassi et al., 1982). Research shows that decreasing the use of craved substances. acetylcholine is involved in the pleasure/reward pathway by The essential amino acid, L-phenylalanine, is also supporting the release of dopamine in the VTA and NAc (Yang et found in Daxitrol. L-phenylalanine can be beneficial for mood and al., 2009; Shirayama & Chaki, 2006). It has been proposed that focus by supporting the synthesis of L-tyrosine (a precursor to cholinesterase inhibitors decrease cravings by increasing dopamine, norepinephrine, and epinephrine) and phenylethylamine acetylcholine in the brain, thereby promoting the binding of the (PEA) (Kusaga et al., 2002). In addition, L-phenylalanine can nicotinic acetylcholine receptor (Alisky, 2006). The binding of enhance satiety in humans by inducing the release of CCK acetylcholine on the nicotinic acetylcholine receptor can promote (Ballinger & Clark, 1994; Pohle-Krauza et al., 2008), although the dopamine activity and increase pleasurable responses, ultimately, precise mechanism is not completely understood. Increased CCK decreasing the need for rewarding stimuli (Alisky, 2006; Hiranita levels can decrease food intake by enhancing satiety signals that are transmitted from the gastrointestinal system to the brain The vagus nerve also utilizes acetylcholine as its (Ballinger & Clark, 1994). Therefore the inclusion of L- primary chemical messenger and provides a source of phenylalanine in Daxitrol helps to promote the feeling of acetylcholine in the brain (Bodenlos et al., 2007a; Bodenlos et al., “fullness” and limit the opportunity to develop cravings. 2007b). As mentioned above, the vagus nerve mediates Forskolin, isolated from the plant Coleus forskohli, can communication between the gastrointestinal system and the brain directly increase the activity of adenylate cyclase (Burns et al., to signal satiety (Bodenlos et al., 2007a; Bodenlos et al., 2007b). 1987). Adenylate cyclase is an enzyme that activates cyclic Therefore, HupA may help facilitate and promote satiety signals in adenosine monophosphate (cAMP), which is a second messenger addition to increasing pleasurable responses to decrease food and *These statements have not been evaluated by the Food and Drug Administration.
This product is not intended to diagnose, treat, cure, or prevent any disease. Individual results may vary.
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Neurological Targets
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Di, C. G. & Imperato, A. (1988). Drugs abused by humans preferentially increase synaptic Cravings can be associated with weight issues, drug dopamine concentrations in the mesolimbic system of freely moving rats. Proc.Natl.Acad.Sci.U.S.A, 85, 5274-5278. use, gambling, and other behaviors. The purpose of Daxitrol is to Dilger, R. N. & Baker, D. H. (2007). Oral N-acetyl-L-cysteine is a safe and effective precursor of cysteine. J.Anim Sci., 85, 1712-1718. not only decrease cravings but also provide the necessary support Diniz, Y. S., Rocha, K. K., Souza, G. A., Galhardi, C. M., Ebaid, G. M., Rodrigues, H. G. et al. to enhance self-control, to limit the consumption of craved stimuli (2006). Effects of N-acetylcysteine on sucrose-rich diet-induceratsd hyperglycaemia, dyslipidemia and oxidative stress in. Eur.J.Pharmacol., 543, and support healthy weight. The ingredients in Daxitrol decrease cravings by supporting dopaminergic, glutamatergic, serotonergic, Dockray, G. J. (2009). Cholecystokinin and gut-brain signalling. Regul.Pept., 155, 6-10. Epstein, L. H. & Leddy, J. J. (2006). Food reinforcement. Appetite, 46, 22-25. acetylcholinergic, and peptidergic systems. These biochemical Gendall, K. A., Joyce, P. R., & Sullivan, P. F. (1997). Impact of definition on prevalence of food systems regulate pleasure, reward, motivation, impulsivity, and cravings in a random sample of young women. Appetite, 28, 63-72. satiety. The commonality of all these actions is their role in Godard, M. P., Johnson, B. A., & Richmond, S. R. (2005). Body composition and hormonal adaptations associated with forskolin consumption in overweight and obese men. cravings. Overall, Daxitrol is a novel and unique dietary supplement that targets various biochemical mediators to decrease Goldstein, R. Z. & Volkow, N. D. (2002). Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am.J.Psychiatry, 159, 1642-1652. Grant, J. E., Kim, S. W., & Odlaug, B. L. (2007). N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study. Biol.Psychiatry, 62, 652-657. REFERENCES
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