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Food Addictions
C H A P T E R
79 Food Addictions Mark S. Gold, Richard L. Shriner College of Medicine, University of Florida, Gainesville, FL, USA
O U T L I N E Definition
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Magnitude of the Problem
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Supportive Evidence Genetic Neuroanatomic/Neuroimaging Neurochemical Stimulus/Reward Paradigms Psychological Research
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DEFINITION Establishing a workable definition for food addiction is of paramount importance to understanding one of the world’s most pressing epidemics, obesity. This definition must also lend greater definition to other forms of food addiction such as binge eating, bulimia, anorexia, and other maladaptive relationships with food. If food is to be seen as a putative agent for addiction and obesity, then we must simultaneously entertain it in a framework not unlike other substances of addiction. A working definition of food addiction should identify a distinguishing set of characteristics that sets it apart from normal eating. It must clearly outline a distinct pattern of behavior that is truly unhealthy (i.e. maladaptive) over space and time. Such a definition is offered below. Importantly, food addiction (like other addictions) involves a dual biasing valence of both perception (i.e. a highly valued [rewarding] substance) and behavior (i.e. craving/dependency), which reliably sets up the abuser and food addict to predictably suffer a set of unhealthy outcomes. In terms of Diagnostic and statistical manual of mental disorders 4th edition text revision (DSM-IV-TR), researchers have argued that food (like gambling) is indeed an addictive substance. They argue that food fulfills the seven Principles of Addiction, Volume 1 http://dx.doi.org/10.1016/B978-0-12-398336-7.00079-6
Clinical Case Examples
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T2DM and Why Food Addictions Matter A Model of Pro-inflammation and Energy Misalignments Clinical Presentation Current Treatments
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Future Research
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DSM-IV-TR criteria of substance dependence. This includes three or more of the following seven criteria realized over a period of at least 12 months: (1) tolerance, (2) withdrawal, (3) the substance is taken in larger amounts for a longer duration than initially intended, (4) attempts are made to cut back on the substance, (5) excessive time is spent pursuing, using, or recovering from the substance, (6) there is curtailment of other activities because of use of the substance, and (7) there is the continued use of the substance despite adverse consequences that are caused by the substance. In terms of practical clinical interventions, we offer the following working definition for food addiction:
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Food addiction represents a pervasive and enduring pattern of both food perception and food-related behavior (leading to either excessive food ingestion or aversion) whose dual valence (i.e. perception and behavior) biases interaction with food in harmful and unhealthy ways. Such a biasing and unhealthy valence toward food continues, despite knowledge of its harmful consequences. Food addicts usually present both a tolerance (i.e. a need to increase participation in their harmful relationships with food over space and time) as well as a form of withdrawal (i.e. an inability to escape their addiction with food without suffering undue anxiety, craving, or other adverse neurochemical reactivity [which may include depression or anger]) when deprived of access to addictive foods. This latter emotional and behavioral reactivity must reliably occur during efforts to either alter or disrupt the food addict’s harmful and maladaptive pattern of eating.
Copyright Ó 2013 Elsevier Inc. All rights reserved.
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The advantage of this definition is that unlike other forms of addiction, ultimate food sobriety (defined later) is clinically understood to be neither absolute nor static, but rather relative and dynamic. Using this sort of dynamic conceptualization of living in balance with food (instead of being captured by its pathological valences causing fixed weight gain, pathological weight flux or loss) the term Living with Food seems justifiable and clinically useful. This living or healthy coexistence with food involves a state of dynamic interaction that implies neither dependency nor addiction, but rather food sobriety and health. Such sobriety connotes a new, dynamic, and more resilient relationship with food that allows for a healthy acquisition and maintenance of weight over space and time. This is done by balancing those valences that would otherwise cause a person to tend toward pathological patterns of eating. Such pathological patterns having genetic, anatomic, neurochemical, psychological, and environmental roots and triggers, are described under the rubric of disordered eating. These disorders include a spectrum reaching from obesity to binge eating to bulimia and then on to anorexia. This newly formulated, dynamic definition of food addiction paves the way for the study of the entire spectrum of disordered eating under a common defining schema, from excessive weight gain (obesity), to periodic weight gain (binge eating and/or bulimia), to excessive weight loss (anorexia).
experienced medical costs five times higher than nonobese counterparts. The world picture in terms of obesity and food addictions (especially for high carb/high fat food (cafeteria style or highly palatable food)) is no better. Rates of obesity have tripled in the last 20 years in the developing world with 10% of the world’s children currently overweight or obese. Countries facing the greatest challenges include the Middle East, Pacific Islands, Southeast Asia, and China. Amongst major world powers, McDonalds (in 6 out of 11 countries) is the favorite fast food chain, with China favoring Kentucky Fried Chicken (KFC). In terms of obesity, the body mass index (BMI) for US children at the 95th percentile is below that in China. Australian and UK women are rapidly approaching the BMIs found in US women. Amongst children in the major countries of the United States, United Kingdom, Australia, and China, Chinese children have gained the marginally highest, some 5-point increase in BMI since 1991. Three things are now selfevident: (1) the major type of diabetes is T2DM, (2) T2DM is largely preventable through weight loss, and (3) T2DM is the number one cause of death in the United States. Hence, the cycle of obesity, diabetic misery, and death tells us food addictions play an ever more critical role in the survival of our species. This cycle goes on and on unabated. The Morbidity and Mortality Weekly Report (MMWR) August 2010 report found that rates of obesity have increased by 1.1% since 2007, negating any prior reports of a leveling off of the obesity epidemic.
MAGNITUDE OF THE PROBLEM If we assume that food addiction plays a potent role in obesity (an assumption that now appears quite plausible) and obesity is the single most common cause of type 2 diabetes mellitus (T2DM), then food addiction may be the most singularly important addiction of our time. In this way, food addictions will continue to vex scientists, minions of public health policy, insurance companies, the Federal Government, and tax payers who will be asked to cover an ever-escalating health care budget as more graduate into the ranks of obesity. Here are some sobering statistics. By 2018, more than 43% of US citizens will be obese. Morbid obesity is one of the fastest growing disease states. The National Council on Compensation Insurance found that • obese claims were roughly three times more expensive; • added treatments related to obesity can balloon cost differences by as much as 30 times; • workers who are morbidly obese filed 45% more claims, missed eight times more work, and
SUPPORTIVE EVIDENCE Supportive evidence for food addiction comes from the following lines of research: • • • • • •
Genetic Neuroanatomic/neuroimaging Neurochemical Stimulus/reward paradigms Psychological research Clinical case examples
Genetic Genetic contributions to food addiction seem plausible given the fact that addiction has an estimated heritability of 50–70%. Various researchers have described how such genetic factors are at play in the dysmorphic syndromes of Prader-Willi, Cohen, Carpenter, and others, as well as leptin/receptor mutation, b3 AR mutation and the overexpression of neuropeptide Y (NPY). Each one of these genetic syndromes
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SUPPORTIVE EVIDENCE
results in obesity and can be seen to exacerbate food addictions in the individuals that are so afflicted. As described later in the neurochemical section, dopamine plays a critical role in addiction. The neurogenetics of dopaminergic receptor supersensitivity and brain reward circuitry continues to emerge. For example, a plethora of animal models are being used to elucidate the role that genetics plays in both animal and human vulnerability to addiction in terms of their responsiveness to food or cocaine.
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Neuroanatomic and neuroimaging studies that are germane to understanding food addiction continue to be developed. Investigators have shown how (using positron emission tomography [PET] and [18F]fluorodeoxyglucose [FDG]), morbidly obese patients have increased metabolism in the somatosensory cortex. They have also showed using PET and FDG in normal weight individuals how increased dopamine increases metabolism in the orbitofrontal cortex and is directly involved with the perception of hunger and desire for food. Using group averaged images of [11C] raclopride PET scans, these same researchers have been able to show that obese rats have marked diminution of dopamine transporter levels compared with nonobese controls. This suggests downregulation of the dopamine (D2/D3) receptor function in obese subjects. This has been replicated in humans. Over the last decade, we now have a greater appreciation for the science of food addiction, including two distinctive food addictive pathways involving: (1) the homeostatic and (2) the reward (or hedonistic) circuits of the brain. Functional magnetic resonance imaging (fMRI) studies have revealed how food craving is activated specifically through three distinct areas of the central nervous system (CNS): hippocampus, insula, and caudate.
withdrawal, craving, and sensitization that can be used to define food addiction (as well as addictions in general). Again, investigators have found the three key neurotransmitters (dopamine, opioids, and acetylcholine) play a pivotal role in the development and maintenance of food addiction through time. Currently, a major focus of study involves the role that intermittent excessive carbohydrate/cafeteria style (fast food) ingestion may have on binge eating. Specifically, rats exposed to excessive amounts of sugar, which were then denied access to such sugar, tended to engage in binge eating over time, versus rats that were given continuous access to such high carbohydrate food (see below). Continuing along this line of investigation, binge eating is also associated with stress. Together with an intermittent exposure to palatable foods (e.g. eating fast foods on an intermediate basis), the evolution of binge eating resulting in the exacerbation of weight seems to reliably involve opioid chemistry interaction within the nucleus accumbens of the brain, along with specific dopamine inputs. Increasingly, animal models for the neurochemistry of food addiction (especially involving sugar) are proving the existence of a craving–bingeing–withdrawal–craving cycle. Researchers in the area of food addiction have described how sugar bingeing works through the combined inputs of dopamine interacting with acetylcholine to affect the net output of g-aminobutyric acid (GABA), all within the nucleus accumbens. Then, this GABA neurochemical traffic goes on to mediate either approach (increased appetite) or avoidance (decreased appetite). In this way, acetylcholine may work to oppose the stimulating effects that dopamine has on appetite. Interestingly, these same researchers found that although both sugar and fat can be associated with bingeing, only sugar was associated with the classic signs of withdrawal, as one would expect from a truly addictive substance.
Neurochemical
Stimulus/Reward Paradigms
Shadowing the progress of understanding food addictions through neuroimaging of the brain, our neurochemical understanding of food addition and disordered eating continues to be elucidated. In terms of the recent worldwide obesity epidemic, this includes how appetite control and energy balance have been adversely affected by large amounts of high energydense foods (e.g., high fructose corn syrup [HFCS]), increased exposure to powerful food cues (e.g. television advertising), together with sedentary lifestyles to create an imbalance between repletion signals versus reward-driven brain inputs leading to obesity. Researchers are focusing on the processes of bingeing,
Stimulus/reward paradigms involving neurobiological pathways and putative neurochemical agents for food addictions are now solidly in play. Again, investigators have shown the significance of addiction to food and brain reward systems. They argue that opioid-based neuropharmacology may underlie the mechanisms behind our current over consumption of palatable (i.e. high carb/high carb, high fat) foods. In general, most research points to the fact that opioid stimulation increases the pleasurable aspects of food, while opioid antagonists do the opposite. At least for carbohydrate craving, opioids may decrease oxytocin-mediated satiety (oxytocin normally turns off carbohydrate
Neuroanatomic/Neuroimaging
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cravings). Thus, opioids may help to mediate the food reward value of carbohydrates. This includes sugarinduced upregulation of m-opioid and D1 dopamine receptors, along with an increase in release of dopamine in the nucleus accumbens. In fact, in rat models, sucrose is often chosen over cocaine. As we just alluded to above, an emerging body of research suggests that sugar can be highly addictive, causing both craving and bingeing in animal subjects who are denied access to it. To be sure, studies of rats who have been exposed to intermittent schedules of high-dose sugar followed by its sudden removal, can display frank withdrawal (i.e. increased motility, nervousness, etc.) after the opioid antagonist naloxone is administered to them. In humans, opiate-dependent individuals on methadone maintenance report higher consumption of sweets than control subjects. Lastly, in terms of stimulus/reward paradigms, food addictions (including binge eating and obesity) highlight that time and space may play an important part in obesity and food addictions, as we suggested in our definition of food addiction given at the end of the last section. Specifically, the effects of some food stimulus early in our lives may have an effect later in life vis-a`-vis the way we live with food. A recent study was able to demonstrate that if mice were exposed early in their development to high carbohydrate chow, although they did not immediately gain weight, later on in their development they did show increased obesity (over controls) when these same mice were given access to highly palatable food. Thus, early exposure to sugar may have an enduring effect (and/or influence upon) our capacity to suffer from obesity later in life.
a deficient ability to experience natural reward. Given that patients with Taq1Aþ allele function have a hypoactive reward system, these same individuals may be susceptible to low food stimulus/reward functionality. Thus, these same individuals may need to consume larger amounts of food to achieve the same measure of reward that those with A1 allele function require. This leaves Taq1Aþ allele cohorts at risk for over ingestion and obesity. At least for some individuals with a high BMI, this has been confirmed. The m-opioid receptor gene (OPRM1) has been extensively studied for drug abuse. This distinct genotype may be higher in binge eaters, but perhaps not in obese individuals without binge eating disorder. Other studies have examined the psychological effects on obesity and food addiction that carbohydrates may have on female subjects suffering depression. As we mentioned in our definition at the end of the last section, individuals suffering from food addiction may undergo both anxiety and/or depression when they face the prospect of food withdrawal. This, of course, forms the withdrawal component within the definition of food addiction. Investigators have been able to show that after inducing dysphoric mood in overweight female subjects, carbohydrate beverages (but not taste-matched protein substitutes) were able to effectuate an antidepressant effect. In other words, carbohydrates (in contrast to matched taste proteins) were able to assuage the carbohydrate cravings these dysphoric females were suffering from, suggesting that carbohydrate ingestion medicates mildly dysphoric mood.
Psychological Research
The last area of evidence that supports the existence of food addiction involves clinical case examples in general medicine; specifically, how stress and stressrelated medical disorders may be involved with carbohydrate cravings and addictions. As we stated earlier, stress plays a crucial role in animal models of binge eating. To this end, if rats are exposed to food restriction alone, they did not tend to overeat. But if one adds the stress of foot shock trauma, these same rats tend to significantly over ingest, especially palatable foods high in carbohydrates and fat. In studies showing this effect, rats needed a primer of at least three restriction/refeeding cycles (see earlier discussion on intermittent exposure to sugar and bingeing), as would be the case in humans for those trying to diet by intermittently restricting their food intake. This is, of course, the same phenomenon we discussed earlier in the rats who were intermittently given access to high carbohydrate chow, followed by restriction. Again, such animals were shown to be at high risk for the eventual development
Another area of evidence that supports food addiction involves psychological research. This involves whether psychological mechanisms play a part in food addictions, albeit as modified by genetic and epigenetic mechanisms. Research is now giving us an interesting glimpse into the possible inputs that psychobiological factors such as reward sensitivity and impulsivity may have on food addictions and obesity/eating disorders. Investigators have recently outlined how genetic inputs to dopamine function (hence food motivation) are translated by way of polymorphisms of the D2 receptor (Taq1A), which may have direct impact on obesity and food addiction. The Taq1Aþ allele has reduced brain dopamine function compared with the A1 allele since those with the Taq1Aþ allele have a 30–40% reduction in D2 receptor density in the striatal region. This has been related to reduced mesolimbic brain dopamine, therefore,
Clinical Case Examples
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T2DM AND WHY FOOD ADDICTIONS MATTER
of binge eating. High stress reactivity binge type eating has also been shown in humans. Food and drugs have cross tolerance in the laboratory and food, especially sugar, is used to calm withdrawing cigarette smokers and addicts. Actual clinical case examples of how food addiction and stress may play a part in everyday medicine comes from research involving models of stress, allostasis, and chronic diseases. The literature on allostatic load refers to the consequences of sustained or repeated activation of mediators of allostasis. Allostasis (literally other balance) is invoked when specific effectors are activated because organismal homeostasis (literally similar balance) is threatened. An example of such an effector might be an interleukin called IL-6, which is a proinflammatory marker in the body. Such inflammatory markers are released when the body undergoes stress. Such stress-induced inflammatory markers tend to be associated with a simultaneous immune response that forces the egress of cortisol from the adrenal gland (perhaps to counteract such effectors). In turn, cortisol can go on to stimulate appetitive function since it has an orexigenic influence on the hypothalamus. Living within this environment, the organism is predisposed to increased hunger, dopamine release, and (as we have learned earlier) increased motivation to seek out food. Thus, stress can through allostatic load, lead to both direct and indirect reactivities in the body that then go on to induce disturbances of appetite and invariably weight gain. In fact, waist to hip ratio (a measure of obesity) as well as glycosylated hemoglobin (a measure of excess blood glucose) are two important indicators of allostatic load. A real-world clinical example of how food addiction, allostatic load, allostasis, and orexigenia might find its way into our lives is found in the disorder called metabolic syndrome. This disorder (again really a syndrome) exists when a patient suffers from at least three of the following: (1) hypertension, (2) hypertriglyceridemia, (3) decreased high-density lipoprotein fraction, (4) hyperglycemia; and (5) obesity. In the case of food addiction, continued cravings for especially high carbohydrate substances continue to inflame body effectors (e.g. IL-6, tumor necrosis factor (TNF), etc.) ultimately causing the exhaustion of insulin-producing cells in the pancreas leading to the number one cause of diabetes, T2DM. Regardless, these sorts of metabolic imbalances can lead to obesity and diabetes, which increase the vulnerability of an individual to stress, which creates a vicious cyclical mechanism between stress, food addictions, obesity, diabetes, leading to more stress. As if this were not enough, stressful life events are known to accelerate the course of diabetes in adverse ways. Since diabetes costs approximately 2.5 times more than any other disorder to treat,
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diabetes, obesity, food addiction, and runaway health care costs remain inextricable from one another.
T2DM AND WHY FOOD ADDICTIONS MATTER A Model of Pro-inflammation and Energy Misalignments The reason food addictions matter, at least in terms of their impact on obesity and medical economics in general, is that obesity is so insidiously and directly associated with T2DM, the number one killer in the United States, if not soon the entire world. Certain endocrinologists have pointed out that food (in particular, HFCS) and other substances of addiction (e.g. ethanol) have many metabolic perturbating and allostatic (see earlier discussion) disease-contributing effects in common. These same endocrine researchers convincingly argue that both HFCS and ethanol (EtOH) can contribute to hyperlipidemia, hepatic inflammation, and hepatic (if not also skeletal) insulin resistance. This leads to increasing feedback-mediated hyperinsulinemia (i.e. to compensate for insulin receptor resistance (insensitivity) in order to preserve organismic metabolic integrity) which eventually exhausts b-cell pancreatic function, often leading to T2DM, if not eventually type 1 diabetes in selected individuals. When it comes to food addiction and its impact on obesity, research is teasing out a common thread between foods of abuse and their impact on several key metabolic, endocrine, and neuroendocrine pathways. These processes and pathways seem to involve the following unraveling of healthy hepatic metabolic eustasis (meaning literally good balance): • exotic (not previously available to Homo sapiens) nutrient energy excess (e.g. HFCS); • ensuing perturbations of hepatic metabolic function; • stimulation of proinflammatory species leading to hepatic insulin resistance; • overwhelmed metabolic pathways that stimulate hepatic gluconeogenesis; • overwhelmed metabolic pathways that stimulate hepatic dyslipidemia; • resultant hypersecretion of insulin which favors development of T2DM; • resultant hypersecretion of insulin which favors fatty acid storage; • skeletal muscle insulin resistance/hyperlipidemia that decreases energy expenditure; • net weight gain due to decreased fatty acid mobilization from adipocyte to muscle; • long-term leptin resistance caused by hyperlipidemia causing further hyperphagia;
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• hyperuricemia from excess ADP breakdown causing NO causing blood pressure; • all of the above contributing to metabolic syndrome and preventable death. The most potent exotic source of nutrition that has arrived on the landscape of the modern Homo sapiens is HFCS. This inflaming source of energy causes several specific perturbations in hepatic function that have been identified by key researchers in the study of endocrinology and obesity. These same researchers have done a masterful job of pointing out the similarities between the addictive substrate EtOH and HFCS. Specifically, how each of these two addictive substances can cause proinflammatory changes, possible reactive oxygen species (ROS), dyslipidemia, and ensuing insulin resistance. EtOH, by altering GABA and opioid transmission within the ventral tegmental area and central areas of the amygdala, activates dopamine neurotransmission. As we mentioned earlier, the stimulation of both opioid and dopamine receptor function is the same thing that carbohydrates (including fructose) are capable of doing and is a prerequisite for defining a substance as addictive. In this way, sugar, EtOH, HFCS, and other potential addictive substances affect not only peripheral organs, but central nervous nuclei as well. Collectively, these and other addictive substances have been shown to cause the stimulation of a host of proinflammatory substances. Such substances are known to be perturbated in an allostatic fashion, which collectively reflect a state of metabolic dysresiliency called the metabolic syndrome. Woven into this syndrome is diabetes, obesity, hypertension, and dyslipidemia, all reflecting a state of hyperoxidative distress. During such states of oxidative organismic dysfunction, adiponectin levels drop while IL-6, TNF, and other proinflammatory markers are increased. In terms of food addictions, it is this state of metabolic dysfunction or stress (what we have chosen to call metabolic dysresiliency) that identifies a state of abuse for the obese food addict. The qualifier (and/or proinflammatory quantifier) that outlines a state of abuse in terms of food addiction is found in the net energy expenditure variables that lead to either metabolic resiliency (when energy intake and energy expenditure are resiliently matched to maintain an adaptive dynamic weight called eubaria) or when they are in nonresilient allostasis reflecting a maladaptive weight that is either hypobariac (e.g. anorexia) or hyperbariac (e.g. obesity). A heterobariac weight would be found in the bulimic individual who although maintaining a normal weight is nonetheless still living in a state of dysresiliency that betrays underlying metabolic distress. This is why these individuals often suffer
from neuropsychiatric disease states that reflect hypothalamic–pituitary–adrenal axis abnormalities (e.g. increased level of corticotropin-releasing factor) such as depression and/or anxiety. At least for the hyperbariac conditions such as simple overweight and obesity, food addictions that lead to a state of abuse invariably lead to metabolic dysresiliency and dysfunction. These metabolic dysresilient states are often, unfortunately, self-sustaining since they tend to disturb and upset the normal balance of anorexigenic/orexigenic endocrine feedback (e.g. food addictions causing obesity, block leptin, hence the body’s normal anorexigenic responsiveness, etc.). With reference to the term sobriety, it follows that food sobriety would reflect a state of eubaria and/or metabolic resiliency. To that end, we can define the term food sobriety in the following way: Food sobriety is a dynamic state of interactivity with food that maintains a healthy balance of resilient metabolic function that is free of significant symbolic (relational) or hedonistic (addictive) skew.
In terms of obesity and T2DM, such a healthy balance of metabolic function or metabolic resilience can be defined as a ratio of insulin to glucagon that is kept in a dynamic (pulsatile) adaptive flux. This flux is necessary for normal hepatic and pancreatic function to work in healthy synergy with one another. This is reflected by a pattern of food ingestion that creates a normal adiponectin and a low proinflammatory oxidative state. To be sure, research has found that the normal healthy pancreas releases insulin in a dynamic, somewhat chaotic fashion that is pulsatile and continuously adaptive, in a nonlinear fashion. This is, of cours, a state much different than that emulated by taking pills or injections to regulate insulin via pharmaceuticals. Even insulin pumps cannot possibly totally emulate this nonlinear continuously adaptive, unpredictable moment to moment resilient flux of insulin versus glucagon that the native healthy pancreas is able to engineer. Therefore, all present and future medical interventions must emphasize the importance of salvaging and restoring native hepatic and pancreatic functioning whenever possible. This, of course, is not always possible, often making permanent and ongoing pharmacotherapy mandatory, if not lifesaving.
Clinical Presentation The clinical presentation of food addiction is obviously both global and omnipresent. Food addictions start with the way we offer nutrition and take care of our children and end in nursing homes and hospitals, which are, even now, overwhelmed by growing numbers of patients dying of metabolic syndrome and T2DM. We need to do a better job of early intervention,
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translational medicine, and more aggressive treatment in terms of patient and physician information sharing, dietary intervention, exercise incentivization, stress/ wellness intervention, and psychobiological/psychological evaluation and treatment. The most important initial assessment in the diagnosis of patients suffering from food addiction is the history and physical examination. At our obesity clinics at the University of Florida, patients are asked to fill out an extensive bariatric data packet. This packet includes background data on current stresses, past stresses (including childhood trauma), past medical and surgical history, past psychiatric history, participation in either Overeaters Anonymous, Alcoholics Anonymous, Weight Watchers, or other fellowship programs, past and current medication, a figurine analysis of the patient’s perceptions of their body image, a patientgenerated narrative of their self-image, a thorough life–weight profile beginning in childhood up until the present, a canvassing of types of foods eaten, frequency and amount, assessment of binge eating and other eating disorders (e.g. laxative, diuretic abuse, self-induced vomiting, etc.), a list of all diets and diet supplement/ diet pill pharm trials, a sleep apnea assessment, inquiry about reasons patient feels they are overweight, and a series of brief psychiatric rating scales. The packet is quite easy to fill out and provides our staff with invaluable data that might otherwise not be assayed. Next, patient’s blood and urine are carefully assessed, including a complete fasting metabolic panel, complete blood count, thyroid functions, fasting insulin, and C-reactive protein. Each patient’s QUICKI score is calculated to assess a raw estimate of insulin resistance. In addition, we may or may not obtain IL-6 and adiponectin titers . After obtaining suitable blood and urine chemistries, weight, electroencephalogram, etc., to assay for disturbances in metabolic function, all our patients are given a cognitive assessment, which helps us discern exactly how they negotiate health care information under stress. Using a cognitive assessment tool allows today’s modern bariatrician to interact with patients in terms of their own biases and unique modes of interacting with food. These biases can often be shown to interfere with a patient’s capacity to overcome their food addiction. Patients should be taught how certain foods, along with their time/space ingestion patterns (see earlier discussion on intermittent schedules of feeding) can lead to hedonistic problems with food, which can then lead to binge eating and other maladaptive ingestion patterns. Finally, patients should be taught how ingesting large quantities of carbohydrates (especially HFCS) can create metabolic problems with food sobriety given their capacity to upset insulin to glucagon ratios and damage hepatic metabolic function.
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Giving patients the capability of focusing upon their relationship problems with food sobriety, cognitive tools (such as the IGS-rooms tool we have developed at the University of Florida) helps patients identify their maladaptive relationship patterns not only with food, but also with their relationships with others (at home, at work, and at play). As we mentioned in the section involving the pivotal role that stress plays in maladaptive eating, without such a cognitive assessment and enrollment in group fellowship intervention, patients tend to remain in maladaptive relationships with food. This may be why the vast majority of diets fail over time. These patients, without adequate medical translation tools, have not engineered a complete transformation in their metabolic, addictive, and relationship interactions with food. This makes food sobriety difficult, if not impossible. After completing a cognitive assessment, patients should undergo a thorough dietary evaluation that helps to quantify and qualify the exact ratios of fats, proteins, and carbohydrates they are ingesting in a typical day. Effort should be made to assist the patient in minimizing their exposure to HFCS as well as large quantities of EtOH for reasons clearly spelled out above. This is exactly why food addiction programs fit comfortably alongside alcohol and other polysubstance abuse interventions. Next, any underlying neuropsychiatric dysfunctions should be addressed via pharmacological and/or psychotherapeutic intervention. Whenever possible, patients should be offered group fellowship interventions. Such group interventions can explore maladaptive patterns of thinking and relating to food. These patterns are then reset into more resilient or adaptive complexes. The group process can then reinforce through group fellowship an enduring participation and validation of more resilient and adaptive interactions with food. Since much of the literature on food addictions seems to support the notion that high carbohydrate/cafeteria style foods (especially when periodically curtailed in repetitive attempts at dieting) create more binge eating than weight loss, programs should generally support continuous feeding throughout the day. The overall goal with patients should be to achieve a relatively low carbohydrate/ reasonably high protein/reasonable medium chain fatty acid diet. Supplementing a patient’s diet with low carbohydrate/reasonably high protein whey protein shakes also seems worthwhile. Rapidly absorbed proteins such as whey protein have been shown to help mitigate hunger. Such a low carbohydrate/high protein caloric source does not tend to aggravate insulin production. Finally, in order to mitigate ongoing inflammation, omega 3 fish oil augmentation would seem advisable in patients wishing to mitigate the proinflammatory responses secondary to their obesity.
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The typical food addict is often a patient who has T2DM and/or a patient who is manifestly obese. This includes bariatric surgical patients (who usually have BMI >40 kg m2). However, clinicians will also discover food addictions in heterobariac patients (defined above), whose BMI is between 17.5 and 25 kg m2. Obviously, such patients may suffer from either borderline anorexia nervosa (i.e. just above 17.5 kg m2) or bulimia (with a normal BMI). In addition, binge-eating patients are obviously found nested within general obese patient populations, representing (conservatively) some 5% of these patients. It has been suggested by various investigators that binge eaters have more intrinsic neuropsychiatric disturbances than those who suffer from non–binge-eating obesity. Others who may suffer from food addictions include patients with polycystic ovaries syndrome, chronic pain (especially those who suffer from concomitant problems with opioid addictions), chronic pulmonary disease, various plegic or paretic disorders leaving them wheelchair bound, patients who are cardiovascular compromised, female rather than male (worldwide, females tend to be more obese than their male counterparts), postpartum patients, etc. Interestingly, certain investigators have shown that morbid obesity is often not associated with alcoholism. Overeating may compete with alcohol for brain reward sites, making alcohol ingestion less reinforcing.
Current Treatments The treatment of food addiction is complicated by the diagnosis. Are there one or many types of food addictions? Is fat preference and overeating a different or related form of sugar and desert-loving food addiction? Only additional research will tell. Multimodal treatment is the norm, extending from group fellowship intervention, to individual psychotherapy, to strategic diet targeting, to focused exercise to bariatric surgical intervention to specific target psychopharmacology. The various antiobesity pharmacologic reagents (A-OPRs) are as diverse as the organs these drugs seek to influence to carry out their anorexigenic response. In terms of the CNS, A-OPRs include bupropion, the serotonin noradrenaline reuptake inhibitor (SNRI) antidepressant (Wellbutrin). This antidepressant effectuates weight loss via its pro-opiomelanocortin (POMC) activator properties. More recently, naltrexone (an opioid receptor antagonist) has been coupled with bupropion to augment bupropion’s POMC activator potency. The anticonvulsants topiramate (Topomax) and zonisamide (Zonegran) have shown some success. Phentermine (Adipex) is a stimulant but only has US Food and Drug Administration (FDA) indications for short-term use only. Unfortunately, patients usually quickly regain weight after discontinuation of the drug. Sibutramine
(Meridia) is a central norepinephrine/serotonin reuptake inhibitor whose use is limited by possible hypertensive side effects. Together with orlistat (see below), sibutramine is the only FDA-approved medication for weight loss. Rimonabant (Acomplia) is an endocannabinoid type 1 inhibitor that was taken off the market because of significant neuropsychiatric side effects including suicidal ideation. More recently, DOPA 3 agonists have been in development and may have potential value in impulsive behavioral diatheses such as cigarette addiction. Some investigators are now considering these same reagents in the treatment of binge eating. In terms of the gut, orlistat (Xenical) is a lipase inhibitor that impairs the digestion of fat causing some degree of malabsorption and weight loss. Its use is limited by the emergence of fatty stools and bowel leakage. Experimental A-OPRs in various phases of development include obinepitide (a dual analogue of PYY3-36 from the distal gut’s L cells and PP from the F cells of the pancreas), GLP-1, OXM (Oxyntomodulin, which contains glucagon and is a potent central acting anorexigenic agent), and others. Metformin (Glucophage) blocks hepatic gluconeogenesis and may help to mitigate the harmful effects that excessive hyperinsulinemia has on leptin function (as we outlined above). Unfortunately, because it does block hepatic gluconeogenesis, metformin will invariably prevent a patient from reestablishing normal metabolic resiliency after they lose sufficient weight. Therefore, it is one of those reagents that is often taken off board in our patients who achieve food sobriety. Bariatric surgery is perhaps the most definitive and effective intervention used to treat patients suffering from morbid obesity (BMI >40 kg m2) and/or patients with a BMI of 35 kg m2 or greater who also suffer from metabolic syndrome. At least for gastric bypass surgery, it is felt that the anatomic rearrangements so engineered by the surgery help to decrease the influence of the gastric hormone ghrelin (which stimulates appetite at the level of the hypothalamus) and increase the output of GLP-1 and PYY, which have the opposite effect. The Diabetic Prevention Study found metformin to be inferior to simple diet and exercise, which represent the ultimate medicinal to fight obesity and prevent T2DM. This is why weight loss means everything to the patient with T2DM or obesity and (at least for obese patients), their food sobriety demands loss of weight. In order to achieve this, many clinicians and researchers are recommending we re-examine our assumptions about the vital role that certain food stuffs play (including HFCS, EtOH in significant quantities, etc.) and the vital role that exercise plays, in stemming the tide of the obesity epidemic. The importance of considering the levels of metabolic (homeostatic), addictive (hedonistic), and relational
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FURTHER READING
(symbolic) drives in patients needs to be integrated into antiobesity/food addiction research and intervention strategies. Without a consideration of all three of these levels of intervention (metabolic, addiction, and relational), simple metabolic revisions are often trumped by addictive attractions (e.g. episodic bingeing on chocolate) or conflicted relational issues (e.g. divorce creating stress and binge eating). Therefore, it is vital that the clinician deals with the entire triad of metabolic–addictive– relational aspects of obesity. Again, this is exactly why the vast majority of weight interventions fail.
FUTURE RESEARCH The future of research in terms of food addictions will only grow in time. First, research on evidence-based diagnostic interviewing and division into treatmentrelevant subgroups is required. In the meantime, the Center for Medicaid and Medicare Services realizes the extraordinary costs of doing nothing. In terms of A-OPRs, the field is wide open. Research on epigenetic modifiers of metabolism will clarify how to more effectively triage those patients who might benefit from a specific gut peptide (such as a ghrelin blocker or GLP-1 modifier), a leptin gene-splicing intervention that ups the level of sensitivity of the leptin hypothalamic receptor, or perhaps a b-3 adipocyte agonist that more effectively uncouples energy expenditure, etc. The potential putative agents for weight loss are more or less endless as are potential genetic interventions in the future. In addition, there is a need to better research more effective bariatric surgical techniques given the likelihood that morbid obesity will only worsen over time. There is also a need to further research our understanding of how human cognitions dealing with stress lead to increased vulnerability to food addictions. This approach needs to be cross culturally relevant. We also need to understand how to better motivate our patients to want to lose weight and afford them the supportive informational structures in order to do so. Social networking will expand in terms of importance, as will research on how to better integrate multispecialty interventions (so-called bundling) for patients suffering from food addictions.
SEE ALSO Gambling, Exercise Dependence, Sexual Addiction, Prenatal Exposure to Alcohol and Illicit Substances, Sensory Imagery in Craving, Craving and Expectancies, Relation of Craving and Appetitive Behavior
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Glossary Acetylcholine chemical substance released from nerve endings to activate muscle, secretory glands, and other nerve cells; a key neurotransmitter. b-3AR specific type of androgen receptor mutation. BMI body mass index (calculated as weight in kilograms divided by the square of height in meters). DSM-IV-TR Diagnostic and statistical manual of mental disorders 4th edition text revision ErOH ethanol GABA g-aminobutyric acid; chief inhibitory neurotransmitter of the vertebrate central nervous system. HFCS High fructose corn syrup. IL-6 interleukin 6; a proinflammatory marker. MMWR Morbidity and Mortality Weekly Report published by the Centers for Disease Control (CDC). NPY neuropeptide Y is a 36-amino acid peptide neurotransmitter found in the brain and autonomic nervous system. Pulsatile beating or throbbing. Syndrome a group of symptoms or signs that, occurring together, produce a pattern typical of a particular disease. T2DM type 2 diabetes mellitus. TNF tumor necrosis factor; a proinflammatory marker. Valence the capacity of something to unite, react, or interact with something else; the degree of attraction or aversion toward/away from something.
Further Reading Avena, N., Rada, P., Hoebel, B., 2008. Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neuroscience and Behavioral Reviews 32, 20–39. Blum, K., Chen, T., Downs, B., et al., 2009. Neurogenetics of dopaminergic receptor supersensitivity in activation of brain reward circuitry and relapse: proposing ‘deprivation-amplification relapse therapy’ (DART). Postgraduate Medicine 121, 176–196. Dagher, A., 2009. Overview: the neurobiology of appetite: hunger as addiction. International Journal of Obesity 33, S30–S33. Davis, C., 2009. Psychobiological traits in the risk profile for overeating and weight gain. International Journal of Obesity 33, S49– S53. Frazier, C., Mason, P., Zhuang, X., Beeler, A., 2008. Sucrose exposure in early life alters adult motivation and weight gain. Public Library of Science 3, e3221. Gearhardt, A.N., Corbin, W.R., Brownell, K.D., 2009. Food addiction: an examination of the diagnostic criteria for dependence. Journal of Addiction Medicine 3, 1–7. Gold, M.S., Graham, N.A., Cocores, J.A., Nixon, S.J., 2009. Food addiction? Journal of Addiction Medicine 3, 42–45. Liu, Y., von Deneen, K.M., Kobeissy, F.H., Gold, M.S., 2010. Food addiction and obesity: evidence from bench to bedside. Journal of Psychoactive Drugs 42, 133–145. Lustig, R., 2010. Fructose: metabolic, hedonic and societal parallels with alcohol. Journal of the American Dietetic Association 110, 1307–1321. Passamonti, L., Rowe, J.B., Schwarzbauer, C., et al., 2009. Personality predicts the brain’s response to viewing appetizing foods: the neural basis of a risk factor for overeating. Journal of Neuroscience 29, 43–51. Pelchat, M., 2009. Food addiction in humans. Journal of Nutrition. 139, 620–622. Wang, G.J., Volkow, N.D., Thanos, P.K., Fowler, J.S., 2009. Imaging of brain dopamine pathways: implications for understanding obesity. Journal of Addiction Medicine 3, 8–18.
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79 Food Addictions Mark S. Gold, Richard L. Shriner College of Medicine, University of Florida, Gainesville, FL, USA
O U T L I N E Definition
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Supportive Evidence Genetic Neuroanatomic/Neuroimaging Neurochemical Stimulus/Reward Paradigms Psychological Research
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DEFINITION Establishing a workable definition for food addiction is of paramount importance to understanding one of the world’s most pressing epidemics, obesity. This definition must also lend greater definition to other forms of food addiction such as binge eating, bulimia, anorexia, and other maladaptive relationships with food. If food is to be seen as a putative agent for addiction and obesity, then we must simultaneously entertain it in a framework not unlike other substances of addiction. A working definition of food addiction should identify a distinguishing set of characteristics that sets it apart from normal eating. It must clearly outline a distinct pattern of behavior that is truly unhealthy (i.e. maladaptive) over space and time. Such a definition is offered below. Importantly, food addiction (like other addictions) involves a dual biasing valence of both perception (i.e. a highly valued [rewarding] substance) and behavior (i.e. craving/dependency), which reliably sets up the abuser and food addict to predictably suffer a set of unhealthy outcomes. In terms of Diagnostic and statistical manual of mental disorders 4th edition text revision (DSM-IV-TR), researchers have argued that food (like gambling) is indeed an addictive substance. They argue that food fulfills the seven Principles of Addiction, Volume 1 http://dx.doi.org/10.1016/B978-0-12-398336-7.00079-6
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DSM-IV-TR criteria of substance dependence. This includes three or more of the following seven criteria realized over a period of at least 12 months: (1) tolerance, (2) withdrawal, (3) the substance is taken in larger amounts for a longer duration than initially intended, (4) attempts are made to cut back on the substance, (5) excessive time is spent pursuing, using, or recovering from the substance, (6) there is curtailment of other activities because of use of the substance, and (7) there is the continued use of the substance despite adverse consequences that are caused by the substance. In terms of practical clinical interventions, we offer the following working definition for food addiction:
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Food addiction represents a pervasive and enduring pattern of both food perception and food-related behavior (leading to either excessive food ingestion or aversion) whose dual valence (i.e. perception and behavior) biases interaction with food in harmful and unhealthy ways. Such a biasing and unhealthy valence toward food continues, despite knowledge of its harmful consequences. Food addicts usually present both a tolerance (i.e. a need to increase participation in their harmful relationships with food over space and time) as well as a form of withdrawal (i.e. an inability to escape their addiction with food without suffering undue anxiety, craving, or other adverse neurochemical reactivity [which may include depression or anger]) when deprived of access to addictive foods. This latter emotional and behavioral reactivity must reliably occur during efforts to either alter or disrupt the food addict’s harmful and maladaptive pattern of eating.
Copyright Ó 2013 Elsevier Inc. All rights reserved.
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The advantage of this definition is that unlike other forms of addiction, ultimate food sobriety (defined later) is clinically understood to be neither absolute nor static, but rather relative and dynamic. Using this sort of dynamic conceptualization of living in balance with food (instead of being captured by its pathological valences causing fixed weight gain, pathological weight flux or loss) the term Living with Food seems justifiable and clinically useful. This living or healthy coexistence with food involves a state of dynamic interaction that implies neither dependency nor addiction, but rather food sobriety and health. Such sobriety connotes a new, dynamic, and more resilient relationship with food that allows for a healthy acquisition and maintenance of weight over space and time. This is done by balancing those valences that would otherwise cause a person to tend toward pathological patterns of eating. Such pathological patterns having genetic, anatomic, neurochemical, psychological, and environmental roots and triggers, are described under the rubric of disordered eating. These disorders include a spectrum reaching from obesity to binge eating to bulimia and then on to anorexia. This newly formulated, dynamic definition of food addiction paves the way for the study of the entire spectrum of disordered eating under a common defining schema, from excessive weight gain (obesity), to periodic weight gain (binge eating and/or bulimia), to excessive weight loss (anorexia).
experienced medical costs five times higher than nonobese counterparts. The world picture in terms of obesity and food addictions (especially for high carb/high fat food (cafeteria style or highly palatable food)) is no better. Rates of obesity have tripled in the last 20 years in the developing world with 10% of the world’s children currently overweight or obese. Countries facing the greatest challenges include the Middle East, Pacific Islands, Southeast Asia, and China. Amongst major world powers, McDonalds (in 6 out of 11 countries) is the favorite fast food chain, with China favoring Kentucky Fried Chicken (KFC). In terms of obesity, the body mass index (BMI) for US children at the 95th percentile is below that in China. Australian and UK women are rapidly approaching the BMIs found in US women. Amongst children in the major countries of the United States, United Kingdom, Australia, and China, Chinese children have gained the marginally highest, some 5-point increase in BMI since 1991. Three things are now selfevident: (1) the major type of diabetes is T2DM, (2) T2DM is largely preventable through weight loss, and (3) T2DM is the number one cause of death in the United States. Hence, the cycle of obesity, diabetic misery, and death tells us food addictions play an ever more critical role in the survival of our species. This cycle goes on and on unabated. The Morbidity and Mortality Weekly Report (MMWR) August 2010 report found that rates of obesity have increased by 1.1% since 2007, negating any prior reports of a leveling off of the obesity epidemic.
MAGNITUDE OF THE PROBLEM If we assume that food addiction plays a potent role in obesity (an assumption that now appears quite plausible) and obesity is the single most common cause of type 2 diabetes mellitus (T2DM), then food addiction may be the most singularly important addiction of our time. In this way, food addictions will continue to vex scientists, minions of public health policy, insurance companies, the Federal Government, and tax payers who will be asked to cover an ever-escalating health care budget as more graduate into the ranks of obesity. Here are some sobering statistics. By 2018, more than 43% of US citizens will be obese. Morbid obesity is one of the fastest growing disease states. The National Council on Compensation Insurance found that • obese claims were roughly three times more expensive; • added treatments related to obesity can balloon cost differences by as much as 30 times; • workers who are morbidly obese filed 45% more claims, missed eight times more work, and
SUPPORTIVE EVIDENCE Supportive evidence for food addiction comes from the following lines of research: • • • • • •
Genetic Neuroanatomic/neuroimaging Neurochemical Stimulus/reward paradigms Psychological research Clinical case examples
Genetic Genetic contributions to food addiction seem plausible given the fact that addiction has an estimated heritability of 50–70%. Various researchers have described how such genetic factors are at play in the dysmorphic syndromes of Prader-Willi, Cohen, Carpenter, and others, as well as leptin/receptor mutation, b3 AR mutation and the overexpression of neuropeptide Y (NPY). Each one of these genetic syndromes
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SUPPORTIVE EVIDENCE
results in obesity and can be seen to exacerbate food addictions in the individuals that are so afflicted. As described later in the neurochemical section, dopamine plays a critical role in addiction. The neurogenetics of dopaminergic receptor supersensitivity and brain reward circuitry continues to emerge. For example, a plethora of animal models are being used to elucidate the role that genetics plays in both animal and human vulnerability to addiction in terms of their responsiveness to food or cocaine.
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Neuroanatomic and neuroimaging studies that are germane to understanding food addiction continue to be developed. Investigators have shown how (using positron emission tomography [PET] and [18F]fluorodeoxyglucose [FDG]), morbidly obese patients have increased metabolism in the somatosensory cortex. They have also showed using PET and FDG in normal weight individuals how increased dopamine increases metabolism in the orbitofrontal cortex and is directly involved with the perception of hunger and desire for food. Using group averaged images of [11C] raclopride PET scans, these same researchers have been able to show that obese rats have marked diminution of dopamine transporter levels compared with nonobese controls. This suggests downregulation of the dopamine (D2/D3) receptor function in obese subjects. This has been replicated in humans. Over the last decade, we now have a greater appreciation for the science of food addiction, including two distinctive food addictive pathways involving: (1) the homeostatic and (2) the reward (or hedonistic) circuits of the brain. Functional magnetic resonance imaging (fMRI) studies have revealed how food craving is activated specifically through three distinct areas of the central nervous system (CNS): hippocampus, insula, and caudate.
withdrawal, craving, and sensitization that can be used to define food addiction (as well as addictions in general). Again, investigators have found the three key neurotransmitters (dopamine, opioids, and acetylcholine) play a pivotal role in the development and maintenance of food addiction through time. Currently, a major focus of study involves the role that intermittent excessive carbohydrate/cafeteria style (fast food) ingestion may have on binge eating. Specifically, rats exposed to excessive amounts of sugar, which were then denied access to such sugar, tended to engage in binge eating over time, versus rats that were given continuous access to such high carbohydrate food (see below). Continuing along this line of investigation, binge eating is also associated with stress. Together with an intermittent exposure to palatable foods (e.g. eating fast foods on an intermediate basis), the evolution of binge eating resulting in the exacerbation of weight seems to reliably involve opioid chemistry interaction within the nucleus accumbens of the brain, along with specific dopamine inputs. Increasingly, animal models for the neurochemistry of food addiction (especially involving sugar) are proving the existence of a craving–bingeing–withdrawal–craving cycle. Researchers in the area of food addiction have described how sugar bingeing works through the combined inputs of dopamine interacting with acetylcholine to affect the net output of g-aminobutyric acid (GABA), all within the nucleus accumbens. Then, this GABA neurochemical traffic goes on to mediate either approach (increased appetite) or avoidance (decreased appetite). In this way, acetylcholine may work to oppose the stimulating effects that dopamine has on appetite. Interestingly, these same researchers found that although both sugar and fat can be associated with bingeing, only sugar was associated with the classic signs of withdrawal, as one would expect from a truly addictive substance.
Neurochemical
Stimulus/Reward Paradigms
Shadowing the progress of understanding food addictions through neuroimaging of the brain, our neurochemical understanding of food addition and disordered eating continues to be elucidated. In terms of the recent worldwide obesity epidemic, this includes how appetite control and energy balance have been adversely affected by large amounts of high energydense foods (e.g., high fructose corn syrup [HFCS]), increased exposure to powerful food cues (e.g. television advertising), together with sedentary lifestyles to create an imbalance between repletion signals versus reward-driven brain inputs leading to obesity. Researchers are focusing on the processes of bingeing,
Stimulus/reward paradigms involving neurobiological pathways and putative neurochemical agents for food addictions are now solidly in play. Again, investigators have shown the significance of addiction to food and brain reward systems. They argue that opioid-based neuropharmacology may underlie the mechanisms behind our current over consumption of palatable (i.e. high carb/high carb, high fat) foods. In general, most research points to the fact that opioid stimulation increases the pleasurable aspects of food, while opioid antagonists do the opposite. At least for carbohydrate craving, opioids may decrease oxytocin-mediated satiety (oxytocin normally turns off carbohydrate
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cravings). Thus, opioids may help to mediate the food reward value of carbohydrates. This includes sugarinduced upregulation of m-opioid and D1 dopamine receptors, along with an increase in release of dopamine in the nucleus accumbens. In fact, in rat models, sucrose is often chosen over cocaine. As we just alluded to above, an emerging body of research suggests that sugar can be highly addictive, causing both craving and bingeing in animal subjects who are denied access to it. To be sure, studies of rats who have been exposed to intermittent schedules of high-dose sugar followed by its sudden removal, can display frank withdrawal (i.e. increased motility, nervousness, etc.) after the opioid antagonist naloxone is administered to them. In humans, opiate-dependent individuals on methadone maintenance report higher consumption of sweets than control subjects. Lastly, in terms of stimulus/reward paradigms, food addictions (including binge eating and obesity) highlight that time and space may play an important part in obesity and food addictions, as we suggested in our definition of food addiction given at the end of the last section. Specifically, the effects of some food stimulus early in our lives may have an effect later in life vis-a`-vis the way we live with food. A recent study was able to demonstrate that if mice were exposed early in their development to high carbohydrate chow, although they did not immediately gain weight, later on in their development they did show increased obesity (over controls) when these same mice were given access to highly palatable food. Thus, early exposure to sugar may have an enduring effect (and/or influence upon) our capacity to suffer from obesity later in life.
a deficient ability to experience natural reward. Given that patients with Taq1Aþ allele function have a hypoactive reward system, these same individuals may be susceptible to low food stimulus/reward functionality. Thus, these same individuals may need to consume larger amounts of food to achieve the same measure of reward that those with A1 allele function require. This leaves Taq1Aþ allele cohorts at risk for over ingestion and obesity. At least for some individuals with a high BMI, this has been confirmed. The m-opioid receptor gene (OPRM1) has been extensively studied for drug abuse. This distinct genotype may be higher in binge eaters, but perhaps not in obese individuals without binge eating disorder. Other studies have examined the psychological effects on obesity and food addiction that carbohydrates may have on female subjects suffering depression. As we mentioned in our definition at the end of the last section, individuals suffering from food addiction may undergo both anxiety and/or depression when they face the prospect of food withdrawal. This, of course, forms the withdrawal component within the definition of food addiction. Investigators have been able to show that after inducing dysphoric mood in overweight female subjects, carbohydrate beverages (but not taste-matched protein substitutes) were able to effectuate an antidepressant effect. In other words, carbohydrates (in contrast to matched taste proteins) were able to assuage the carbohydrate cravings these dysphoric females were suffering from, suggesting that carbohydrate ingestion medicates mildly dysphoric mood.
Psychological Research
The last area of evidence that supports the existence of food addiction involves clinical case examples in general medicine; specifically, how stress and stressrelated medical disorders may be involved with carbohydrate cravings and addictions. As we stated earlier, stress plays a crucial role in animal models of binge eating. To this end, if rats are exposed to food restriction alone, they did not tend to overeat. But if one adds the stress of foot shock trauma, these same rats tend to significantly over ingest, especially palatable foods high in carbohydrates and fat. In studies showing this effect, rats needed a primer of at least three restriction/refeeding cycles (see earlier discussion on intermittent exposure to sugar and bingeing), as would be the case in humans for those trying to diet by intermittently restricting their food intake. This is, of course, the same phenomenon we discussed earlier in the rats who were intermittently given access to high carbohydrate chow, followed by restriction. Again, such animals were shown to be at high risk for the eventual development
Another area of evidence that supports food addiction involves psychological research. This involves whether psychological mechanisms play a part in food addictions, albeit as modified by genetic and epigenetic mechanisms. Research is now giving us an interesting glimpse into the possible inputs that psychobiological factors such as reward sensitivity and impulsivity may have on food addictions and obesity/eating disorders. Investigators have recently outlined how genetic inputs to dopamine function (hence food motivation) are translated by way of polymorphisms of the D2 receptor (Taq1A), which may have direct impact on obesity and food addiction. The Taq1Aþ allele has reduced brain dopamine function compared with the A1 allele since those with the Taq1Aþ allele have a 30–40% reduction in D2 receptor density in the striatal region. This has been related to reduced mesolimbic brain dopamine, therefore,
Clinical Case Examples
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T2DM AND WHY FOOD ADDICTIONS MATTER
of binge eating. High stress reactivity binge type eating has also been shown in humans. Food and drugs have cross tolerance in the laboratory and food, especially sugar, is used to calm withdrawing cigarette smokers and addicts. Actual clinical case examples of how food addiction and stress may play a part in everyday medicine comes from research involving models of stress, allostasis, and chronic diseases. The literature on allostatic load refers to the consequences of sustained or repeated activation of mediators of allostasis. Allostasis (literally other balance) is invoked when specific effectors are activated because organismal homeostasis (literally similar balance) is threatened. An example of such an effector might be an interleukin called IL-6, which is a proinflammatory marker in the body. Such inflammatory markers are released when the body undergoes stress. Such stress-induced inflammatory markers tend to be associated with a simultaneous immune response that forces the egress of cortisol from the adrenal gland (perhaps to counteract such effectors). In turn, cortisol can go on to stimulate appetitive function since it has an orexigenic influence on the hypothalamus. Living within this environment, the organism is predisposed to increased hunger, dopamine release, and (as we have learned earlier) increased motivation to seek out food. Thus, stress can through allostatic load, lead to both direct and indirect reactivities in the body that then go on to induce disturbances of appetite and invariably weight gain. In fact, waist to hip ratio (a measure of obesity) as well as glycosylated hemoglobin (a measure of excess blood glucose) are two important indicators of allostatic load. A real-world clinical example of how food addiction, allostatic load, allostasis, and orexigenia might find its way into our lives is found in the disorder called metabolic syndrome. This disorder (again really a syndrome) exists when a patient suffers from at least three of the following: (1) hypertension, (2) hypertriglyceridemia, (3) decreased high-density lipoprotein fraction, (4) hyperglycemia; and (5) obesity. In the case of food addiction, continued cravings for especially high carbohydrate substances continue to inflame body effectors (e.g. IL-6, tumor necrosis factor (TNF), etc.) ultimately causing the exhaustion of insulin-producing cells in the pancreas leading to the number one cause of diabetes, T2DM. Regardless, these sorts of metabolic imbalances can lead to obesity and diabetes, which increase the vulnerability of an individual to stress, which creates a vicious cyclical mechanism between stress, food addictions, obesity, diabetes, leading to more stress. As if this were not enough, stressful life events are known to accelerate the course of diabetes in adverse ways. Since diabetes costs approximately 2.5 times more than any other disorder to treat,
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diabetes, obesity, food addiction, and runaway health care costs remain inextricable from one another.
T2DM AND WHY FOOD ADDICTIONS MATTER A Model of Pro-inflammation and Energy Misalignments The reason food addictions matter, at least in terms of their impact on obesity and medical economics in general, is that obesity is so insidiously and directly associated with T2DM, the number one killer in the United States, if not soon the entire world. Certain endocrinologists have pointed out that food (in particular, HFCS) and other substances of addiction (e.g. ethanol) have many metabolic perturbating and allostatic (see earlier discussion) disease-contributing effects in common. These same endocrine researchers convincingly argue that both HFCS and ethanol (EtOH) can contribute to hyperlipidemia, hepatic inflammation, and hepatic (if not also skeletal) insulin resistance. This leads to increasing feedback-mediated hyperinsulinemia (i.e. to compensate for insulin receptor resistance (insensitivity) in order to preserve organismic metabolic integrity) which eventually exhausts b-cell pancreatic function, often leading to T2DM, if not eventually type 1 diabetes in selected individuals. When it comes to food addiction and its impact on obesity, research is teasing out a common thread between foods of abuse and their impact on several key metabolic, endocrine, and neuroendocrine pathways. These processes and pathways seem to involve the following unraveling of healthy hepatic metabolic eustasis (meaning literally good balance): • exotic (not previously available to Homo sapiens) nutrient energy excess (e.g. HFCS); • ensuing perturbations of hepatic metabolic function; • stimulation of proinflammatory species leading to hepatic insulin resistance; • overwhelmed metabolic pathways that stimulate hepatic gluconeogenesis; • overwhelmed metabolic pathways that stimulate hepatic dyslipidemia; • resultant hypersecretion of insulin which favors development of T2DM; • resultant hypersecretion of insulin which favors fatty acid storage; • skeletal muscle insulin resistance/hyperlipidemia that decreases energy expenditure; • net weight gain due to decreased fatty acid mobilization from adipocyte to muscle; • long-term leptin resistance caused by hyperlipidemia causing further hyperphagia;
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• hyperuricemia from excess ADP breakdown causing NO causing blood pressure; • all of the above contributing to metabolic syndrome and preventable death. The most potent exotic source of nutrition that has arrived on the landscape of the modern Homo sapiens is HFCS. This inflaming source of energy causes several specific perturbations in hepatic function that have been identified by key researchers in the study of endocrinology and obesity. These same researchers have done a masterful job of pointing out the similarities between the addictive substrate EtOH and HFCS. Specifically, how each of these two addictive substances can cause proinflammatory changes, possible reactive oxygen species (ROS), dyslipidemia, and ensuing insulin resistance. EtOH, by altering GABA and opioid transmission within the ventral tegmental area and central areas of the amygdala, activates dopamine neurotransmission. As we mentioned earlier, the stimulation of both opioid and dopamine receptor function is the same thing that carbohydrates (including fructose) are capable of doing and is a prerequisite for defining a substance as addictive. In this way, sugar, EtOH, HFCS, and other potential addictive substances affect not only peripheral organs, but central nervous nuclei as well. Collectively, these and other addictive substances have been shown to cause the stimulation of a host of proinflammatory substances. Such substances are known to be perturbated in an allostatic fashion, which collectively reflect a state of metabolic dysresiliency called the metabolic syndrome. Woven into this syndrome is diabetes, obesity, hypertension, and dyslipidemia, all reflecting a state of hyperoxidative distress. During such states of oxidative organismic dysfunction, adiponectin levels drop while IL-6, TNF, and other proinflammatory markers are increased. In terms of food addictions, it is this state of metabolic dysfunction or stress (what we have chosen to call metabolic dysresiliency) that identifies a state of abuse for the obese food addict. The qualifier (and/or proinflammatory quantifier) that outlines a state of abuse in terms of food addiction is found in the net energy expenditure variables that lead to either metabolic resiliency (when energy intake and energy expenditure are resiliently matched to maintain an adaptive dynamic weight called eubaria) or when they are in nonresilient allostasis reflecting a maladaptive weight that is either hypobariac (e.g. anorexia) or hyperbariac (e.g. obesity). A heterobariac weight would be found in the bulimic individual who although maintaining a normal weight is nonetheless still living in a state of dysresiliency that betrays underlying metabolic distress. This is why these individuals often suffer
from neuropsychiatric disease states that reflect hypothalamic–pituitary–adrenal axis abnormalities (e.g. increased level of corticotropin-releasing factor) such as depression and/or anxiety. At least for the hyperbariac conditions such as simple overweight and obesity, food addictions that lead to a state of abuse invariably lead to metabolic dysresiliency and dysfunction. These metabolic dysresilient states are often, unfortunately, self-sustaining since they tend to disturb and upset the normal balance of anorexigenic/orexigenic endocrine feedback (e.g. food addictions causing obesity, block leptin, hence the body’s normal anorexigenic responsiveness, etc.). With reference to the term sobriety, it follows that food sobriety would reflect a state of eubaria and/or metabolic resiliency. To that end, we can define the term food sobriety in the following way: Food sobriety is a dynamic state of interactivity with food that maintains a healthy balance of resilient metabolic function that is free of significant symbolic (relational) or hedonistic (addictive) skew.
In terms of obesity and T2DM, such a healthy balance of metabolic function or metabolic resilience can be defined as a ratio of insulin to glucagon that is kept in a dynamic (pulsatile) adaptive flux. This flux is necessary for normal hepatic and pancreatic function to work in healthy synergy with one another. This is reflected by a pattern of food ingestion that creates a normal adiponectin and a low proinflammatory oxidative state. To be sure, research has found that the normal healthy pancreas releases insulin in a dynamic, somewhat chaotic fashion that is pulsatile and continuously adaptive, in a nonlinear fashion. This is, of cours, a state much different than that emulated by taking pills or injections to regulate insulin via pharmaceuticals. Even insulin pumps cannot possibly totally emulate this nonlinear continuously adaptive, unpredictable moment to moment resilient flux of insulin versus glucagon that the native healthy pancreas is able to engineer. Therefore, all present and future medical interventions must emphasize the importance of salvaging and restoring native hepatic and pancreatic functioning whenever possible. This, of course, is not always possible, often making permanent and ongoing pharmacotherapy mandatory, if not lifesaving.
Clinical Presentation The clinical presentation of food addiction is obviously both global and omnipresent. Food addictions start with the way we offer nutrition and take care of our children and end in nursing homes and hospitals, which are, even now, overwhelmed by growing numbers of patients dying of metabolic syndrome and T2DM. We need to do a better job of early intervention,
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T2DM AND WHY FOOD ADDICTIONS MATTER
translational medicine, and more aggressive treatment in terms of patient and physician information sharing, dietary intervention, exercise incentivization, stress/ wellness intervention, and psychobiological/psychological evaluation and treatment. The most important initial assessment in the diagnosis of patients suffering from food addiction is the history and physical examination. At our obesity clinics at the University of Florida, patients are asked to fill out an extensive bariatric data packet. This packet includes background data on current stresses, past stresses (including childhood trauma), past medical and surgical history, past psychiatric history, participation in either Overeaters Anonymous, Alcoholics Anonymous, Weight Watchers, or other fellowship programs, past and current medication, a figurine analysis of the patient’s perceptions of their body image, a patientgenerated narrative of their self-image, a thorough life–weight profile beginning in childhood up until the present, a canvassing of types of foods eaten, frequency and amount, assessment of binge eating and other eating disorders (e.g. laxative, diuretic abuse, self-induced vomiting, etc.), a list of all diets and diet supplement/ diet pill pharm trials, a sleep apnea assessment, inquiry about reasons patient feels they are overweight, and a series of brief psychiatric rating scales. The packet is quite easy to fill out and provides our staff with invaluable data that might otherwise not be assayed. Next, patient’s blood and urine are carefully assessed, including a complete fasting metabolic panel, complete blood count, thyroid functions, fasting insulin, and C-reactive protein. Each patient’s QUICKI score is calculated to assess a raw estimate of insulin resistance. In addition, we may or may not obtain IL-6 and adiponectin titers . After obtaining suitable blood and urine chemistries, weight, electroencephalogram, etc., to assay for disturbances in metabolic function, all our patients are given a cognitive assessment, which helps us discern exactly how they negotiate health care information under stress. Using a cognitive assessment tool allows today’s modern bariatrician to interact with patients in terms of their own biases and unique modes of interacting with food. These biases can often be shown to interfere with a patient’s capacity to overcome their food addiction. Patients should be taught how certain foods, along with their time/space ingestion patterns (see earlier discussion on intermittent schedules of feeding) can lead to hedonistic problems with food, which can then lead to binge eating and other maladaptive ingestion patterns. Finally, patients should be taught how ingesting large quantities of carbohydrates (especially HFCS) can create metabolic problems with food sobriety given their capacity to upset insulin to glucagon ratios and damage hepatic metabolic function.
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Giving patients the capability of focusing upon their relationship problems with food sobriety, cognitive tools (such as the IGS-rooms tool we have developed at the University of Florida) helps patients identify their maladaptive relationship patterns not only with food, but also with their relationships with others (at home, at work, and at play). As we mentioned in the section involving the pivotal role that stress plays in maladaptive eating, without such a cognitive assessment and enrollment in group fellowship intervention, patients tend to remain in maladaptive relationships with food. This may be why the vast majority of diets fail over time. These patients, without adequate medical translation tools, have not engineered a complete transformation in their metabolic, addictive, and relationship interactions with food. This makes food sobriety difficult, if not impossible. After completing a cognitive assessment, patients should undergo a thorough dietary evaluation that helps to quantify and qualify the exact ratios of fats, proteins, and carbohydrates they are ingesting in a typical day. Effort should be made to assist the patient in minimizing their exposure to HFCS as well as large quantities of EtOH for reasons clearly spelled out above. This is exactly why food addiction programs fit comfortably alongside alcohol and other polysubstance abuse interventions. Next, any underlying neuropsychiatric dysfunctions should be addressed via pharmacological and/or psychotherapeutic intervention. Whenever possible, patients should be offered group fellowship interventions. Such group interventions can explore maladaptive patterns of thinking and relating to food. These patterns are then reset into more resilient or adaptive complexes. The group process can then reinforce through group fellowship an enduring participation and validation of more resilient and adaptive interactions with food. Since much of the literature on food addictions seems to support the notion that high carbohydrate/cafeteria style foods (especially when periodically curtailed in repetitive attempts at dieting) create more binge eating than weight loss, programs should generally support continuous feeding throughout the day. The overall goal with patients should be to achieve a relatively low carbohydrate/ reasonably high protein/reasonable medium chain fatty acid diet. Supplementing a patient’s diet with low carbohydrate/reasonably high protein whey protein shakes also seems worthwhile. Rapidly absorbed proteins such as whey protein have been shown to help mitigate hunger. Such a low carbohydrate/high protein caloric source does not tend to aggravate insulin production. Finally, in order to mitigate ongoing inflammation, omega 3 fish oil augmentation would seem advisable in patients wishing to mitigate the proinflammatory responses secondary to their obesity.
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The typical food addict is often a patient who has T2DM and/or a patient who is manifestly obese. This includes bariatric surgical patients (who usually have BMI >40 kg m2). However, clinicians will also discover food addictions in heterobariac patients (defined above), whose BMI is between 17.5 and 25 kg m2. Obviously, such patients may suffer from either borderline anorexia nervosa (i.e. just above 17.5 kg m2) or bulimia (with a normal BMI). In addition, binge-eating patients are obviously found nested within general obese patient populations, representing (conservatively) some 5% of these patients. It has been suggested by various investigators that binge eaters have more intrinsic neuropsychiatric disturbances than those who suffer from non–binge-eating obesity. Others who may suffer from food addictions include patients with polycystic ovaries syndrome, chronic pain (especially those who suffer from concomitant problems with opioid addictions), chronic pulmonary disease, various plegic or paretic disorders leaving them wheelchair bound, patients who are cardiovascular compromised, female rather than male (worldwide, females tend to be more obese than their male counterparts), postpartum patients, etc. Interestingly, certain investigators have shown that morbid obesity is often not associated with alcoholism. Overeating may compete with alcohol for brain reward sites, making alcohol ingestion less reinforcing.
Current Treatments The treatment of food addiction is complicated by the diagnosis. Are there one or many types of food addictions? Is fat preference and overeating a different or related form of sugar and desert-loving food addiction? Only additional research will tell. Multimodal treatment is the norm, extending from group fellowship intervention, to individual psychotherapy, to strategic diet targeting, to focused exercise to bariatric surgical intervention to specific target psychopharmacology. The various antiobesity pharmacologic reagents (A-OPRs) are as diverse as the organs these drugs seek to influence to carry out their anorexigenic response. In terms of the CNS, A-OPRs include bupropion, the serotonin noradrenaline reuptake inhibitor (SNRI) antidepressant (Wellbutrin). This antidepressant effectuates weight loss via its pro-opiomelanocortin (POMC) activator properties. More recently, naltrexone (an opioid receptor antagonist) has been coupled with bupropion to augment bupropion’s POMC activator potency. The anticonvulsants topiramate (Topomax) and zonisamide (Zonegran) have shown some success. Phentermine (Adipex) is a stimulant but only has US Food and Drug Administration (FDA) indications for short-term use only. Unfortunately, patients usually quickly regain weight after discontinuation of the drug. Sibutramine
(Meridia) is a central norepinephrine/serotonin reuptake inhibitor whose use is limited by possible hypertensive side effects. Together with orlistat (see below), sibutramine is the only FDA-approved medication for weight loss. Rimonabant (Acomplia) is an endocannabinoid type 1 inhibitor that was taken off the market because of significant neuropsychiatric side effects including suicidal ideation. More recently, DOPA 3 agonists have been in development and may have potential value in impulsive behavioral diatheses such as cigarette addiction. Some investigators are now considering these same reagents in the treatment of binge eating. In terms of the gut, orlistat (Xenical) is a lipase inhibitor that impairs the digestion of fat causing some degree of malabsorption and weight loss. Its use is limited by the emergence of fatty stools and bowel leakage. Experimental A-OPRs in various phases of development include obinepitide (a dual analogue of PYY3-36 from the distal gut’s L cells and PP from the F cells of the pancreas), GLP-1, OXM (Oxyntomodulin, which contains glucagon and is a potent central acting anorexigenic agent), and others. Metformin (Glucophage) blocks hepatic gluconeogenesis and may help to mitigate the harmful effects that excessive hyperinsulinemia has on leptin function (as we outlined above). Unfortunately, because it does block hepatic gluconeogenesis, metformin will invariably prevent a patient from reestablishing normal metabolic resiliency after they lose sufficient weight. Therefore, it is one of those reagents that is often taken off board in our patients who achieve food sobriety. Bariatric surgery is perhaps the most definitive and effective intervention used to treat patients suffering from morbid obesity (BMI >40 kg m2) and/or patients with a BMI of 35 kg m2 or greater who also suffer from metabolic syndrome. At least for gastric bypass surgery, it is felt that the anatomic rearrangements so engineered by the surgery help to decrease the influence of the gastric hormone ghrelin (which stimulates appetite at the level of the hypothalamus) and increase the output of GLP-1 and PYY, which have the opposite effect. The Diabetic Prevention Study found metformin to be inferior to simple diet and exercise, which represent the ultimate medicinal to fight obesity and prevent T2DM. This is why weight loss means everything to the patient with T2DM or obesity and (at least for obese patients), their food sobriety demands loss of weight. In order to achieve this, many clinicians and researchers are recommending we re-examine our assumptions about the vital role that certain food stuffs play (including HFCS, EtOH in significant quantities, etc.) and the vital role that exercise plays, in stemming the tide of the obesity epidemic. The importance of considering the levels of metabolic (homeostatic), addictive (hedonistic), and relational
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FURTHER READING
(symbolic) drives in patients needs to be integrated into antiobesity/food addiction research and intervention strategies. Without a consideration of all three of these levels of intervention (metabolic, addiction, and relational), simple metabolic revisions are often trumped by addictive attractions (e.g. episodic bingeing on chocolate) or conflicted relational issues (e.g. divorce creating stress and binge eating). Therefore, it is vital that the clinician deals with the entire triad of metabolic–addictive– relational aspects of obesity. Again, this is exactly why the vast majority of weight interventions fail.
FUTURE RESEARCH The future of research in terms of food addictions will only grow in time. First, research on evidence-based diagnostic interviewing and division into treatmentrelevant subgroups is required. In the meantime, the Center for Medicaid and Medicare Services realizes the extraordinary costs of doing nothing. In terms of A-OPRs, the field is wide open. Research on epigenetic modifiers of metabolism will clarify how to more effectively triage those patients who might benefit from a specific gut peptide (such as a ghrelin blocker or GLP-1 modifier), a leptin gene-splicing intervention that ups the level of sensitivity of the leptin hypothalamic receptor, or perhaps a b-3 adipocyte agonist that more effectively uncouples energy expenditure, etc. The potential putative agents for weight loss are more or less endless as are potential genetic interventions in the future. In addition, there is a need to better research more effective bariatric surgical techniques given the likelihood that morbid obesity will only worsen over time. There is also a need to further research our understanding of how human cognitions dealing with stress lead to increased vulnerability to food addictions. This approach needs to be cross culturally relevant. We also need to understand how to better motivate our patients to want to lose weight and afford them the supportive informational structures in order to do so. Social networking will expand in terms of importance, as will research on how to better integrate multispecialty interventions (so-called bundling) for patients suffering from food addictions.
SEE ALSO Gambling, Exercise Dependence, Sexual Addiction, Prenatal Exposure to Alcohol and Illicit Substances, Sensory Imagery in Craving, Craving and Expectancies, Relation of Craving and Appetitive Behavior
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Glossary Acetylcholine chemical substance released from nerve endings to activate muscle, secretory glands, and other nerve cells; a key neurotransmitter. b-3AR specific type of androgen receptor mutation. BMI body mass index (calculated as weight in kilograms divided by the square of height in meters). DSM-IV-TR Diagnostic and statistical manual of mental disorders 4th edition text revision ErOH ethanol GABA g-aminobutyric acid; chief inhibitory neurotransmitter of the vertebrate central nervous system. HFCS High fructose corn syrup. IL-6 interleukin 6; a proinflammatory marker. MMWR Morbidity and Mortality Weekly Report published by the Centers for Disease Control (CDC). NPY neuropeptide Y is a 36-amino acid peptide neurotransmitter found in the brain and autonomic nervous system. Pulsatile beating or throbbing. Syndrome a group of symptoms or signs that, occurring together, produce a pattern typical of a particular disease. T2DM type 2 diabetes mellitus. TNF tumor necrosis factor; a proinflammatory marker. Valence the capacity of something to unite, react, or interact with something else; the degree of attraction or aversion toward/away from something.
Further Reading Avena, N., Rada, P., Hoebel, B., 2008. Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neuroscience and Behavioral Reviews 32, 20–39. Blum, K., Chen, T., Downs, B., et al., 2009. Neurogenetics of dopaminergic receptor supersensitivity in activation of brain reward circuitry and relapse: proposing ‘deprivation-amplification relapse therapy’ (DART). Postgraduate Medicine 121, 176–196. Dagher, A., 2009. Overview: the neurobiology of appetite: hunger as addiction. International Journal of Obesity 33, S30–S33. Davis, C., 2009. Psychobiological traits in the risk profile for overeating and weight gain. International Journal of Obesity 33, S49– S53. Frazier, C., Mason, P., Zhuang, X., Beeler, A., 2008. Sucrose exposure in early life alters adult motivation and weight gain. Public Library of Science 3, e3221. Gearhardt, A.N., Corbin, W.R., Brownell, K.D., 2009. Food addiction: an examination of the diagnostic criteria for dependence. Journal of Addiction Medicine 3, 1–7. Gold, M.S., Graham, N.A., Cocores, J.A., Nixon, S.J., 2009. Food addiction? Journal of Addiction Medicine 3, 42–45. Liu, Y., von Deneen, K.M., Kobeissy, F.H., Gold, M.S., 2010. Food addiction and obesity: evidence from bench to bedside. Journal of Psychoactive Drugs 42, 133–145. Lustig, R., 2010. Fructose: metabolic, hedonic and societal parallels with alcohol. Journal of the American Dietetic Association 110, 1307–1321. Passamonti, L., Rowe, J.B., Schwarzbauer, C., et al., 2009. Personality predicts the brain’s response to viewing appetizing foods: the neural basis of a risk factor for overeating. Journal of Neuroscience 29, 43–51. Pelchat, M., 2009. Food addiction in humans. Journal of Nutrition. 139, 620–622. Wang, G.J., Volkow, N.D., Thanos, P.K., Fowler, J.S., 2009. Imaging of brain dopamine pathways: implications for understanding obesity. Journal of Addiction Medicine 3, 8–18.
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