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Towards a Translational Approach to Food Addiction: Implications for Bulimia Nervosa

Towards a Translational Approach to Food Addiction: Implications for Bulimia Nervosa Purpose of Review In recent years, the food addiction hypothesis of loss-of-control eating has gained traction in the field of eating disorders. In particular, the neural process of food addiction plays a dominant role in the recently formulated “addictive appetite” model of bulimia nervosa and binge eating disorder. Nonetheless, several components of the food addiction hypothesis, including the presence of withdrawal and tolerance effects, as well as the proposition that some foods possess “addicting” properties, remain highly controversial. In response, the current review synthesises existing evidence for withdrawal and tolerance effects in people with bulimia nervosa. Recent Findings The recent development of a validated tool to measure withdrawal from highly processed foods will aid in measuring withdrawal symptoms and testing hypotheses related to withdrawal in the context of food addiction. We subsequently describe preclinical and human evidence for a central insulin- and dopamine-mediated pathway by which recurrent loss-of- control binge eating is maintained in bulimia nervosa. Summary Evidence in populations with bulimia nervosa and loss-of-control eating provides preliminary support for the role of food addiction in the maintenance of bulimia nervosa. Future longitudinal research is needed to develop a clearer profile of illness progression and to clarify the extent to which dysregulation in glucose metabolism contributes to food craving and symptom maintenance in bulimia nervosa. . . . . Keywords Food addiction Bulimia nervosa Eating disorders Sugar Dopamine Background In this article, we will use bulimia nervosa (BN) as the exem- plar. The “Addictive Appetite Model” proposes that three pri- The concept of “food addiction” has received increasing at- mary processes maintain psychopathology in BN: (1) the high tention in the scientific literature of recent years. While cogent salience of palatable foods [3], which is moderated by a ge- arguments have been made against the establishment of food netic susceptibility to food approach tendencies, reduced effi- addiction as a psychiatric diagnosis in its own right [1], there ciency in satiation processes [4] and/or episodes of food re- is substantial evidence to suggest that processes similar to striction; (2) chronic stress and interpersonal difficulties those observed in substance abuse disorders play a significant resulting in a deficiency of alternative rewards and a primed role in the maintenance of eating disorders in which loss of stress system [5]; and (3) large swings in blood glucose, control of eating is a feature (e.g. anorexia nervosa-binge caused by the consumption of foods with a high glycaemic purge type, bulimia nervosa and binge eating disorder) [2� ]. index, self-induced vomiting or insulin resistance (and insulin omission in diabetes mellitus). These pathways may contrib- ute to compulsive binge eating behaviour through aberrations This article is part of the Topical Collection on Food Addiction in dopaminergic function in a similar way to substance addictions. * Monica Leslie The current review presents a synthesis of the literature monica.leslie@kcl.ac.uk investigating some of the controversial aspects of applying the food addiction paradigm to eating disorders. For instance, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), there is uncertainty as to whether tolerance and withdrawal Section of Eating Disorders, King’s College London (KCL), 103 criteria for an addictive disorder as specified within the Denmark Hill, London SE5 8AF, UK Curr Addict Rep (2019) 6:258–265 259 DSM-5 are met. We also present a synthesis of molecular, consumption [13], a finding which may be of particular im- preclinical, clinical and neuroimaging evidence illustrating portance to BN as it is characterised by intermittent fasting how fluxes in glucose and insulin moderate central dopami- and binge episodes [14]. A similar downregulation of dopa- nergic functioning. mine D2 receptors is found in humans addicted to drugs of abuse [15] and is thought to be a key driver of compensatory overconsumption in the Reward Hyposensitivity Theory [16, Does Bulimia Nervosa Meet DSM-5 Criteria 17]. Behavioural observations in people with substance use for an Addictive Disorder? disorders mirror these findings. Individuals with BN endorse higher levels of tolerance-like The DSM-5 criteria for an addictive disorder are presented in symptoms measured using the Yale Food Addiction Scale (YFAS) [8], compared with healthy controls [18, 19]. There Table 1. The extent to which BN meets these criteria has been reviewed extensively elsewhere [6]. In his 2014 review, are clinical reports of subthreshold BN patients initiating larg- er and more frequent binge episodes over time [20]. Brewerton acknowledges significant phenotypic overlap be- tween disorders of substance dependence and BN but high- Consistent with these accounts is cross-sectional evidence of the correlation between higher body weight and frequency and lights a paucity of systematic clinical evidence for tolerance and withdrawal in the latter, a point frequently cited as a major severity of binge eating episodes [21]. Individuals with binge- weakness of the food addiction hypothesis [7]. Much research type eating disorders endorse significantly greater levels of on tolerance and withdrawal symptoms in humans to date has eating for purposes of reward enhancement compared with been largely anecdotal [8]. However, herein we synthesise the weight-matched controls [22]. Such evidence, although com- evidence from new assessment methods. pelling, remains indirect and is insufficient to prove the exis- tence of tolerance in humans. A preference for intensely sweet food and larger quan- Tolerance tities of sweeteners in individuals with BN is a character- istic often presented as an indicator of tolerance [3, The most compelling evidence for food tolerance is demon- strated in animal models, as previously reviewed by Murray 23–25]. Furthermore, this preference remains after ingesting a glucose load [26]. Magnetic resonance imag- et al. [9]. Rats who voluntarily overeat highly palatable food exhibit evidence of a neural reward deficit due to downregu- ing (MRI) studies indicate hypofunctioning of gustatory and limbic circuitry in BN patients when tasting palatable lated dopamine D2 receptors, which worsens as weight is gained [10–12]. This decreased sensitivity to reward is direct- food compared with controls [27, 28] and compared with individuals recovered from BN [29, 30]. This evidence is ly linked to the onset of compulsive food seeking in rats [11]. Repetitive bingeing on sucrose interspersed with periods of consistent with the idea that individuals with BN ingest dietary restriction causes rats to triple their overall daily sugar more food over time because of a decreased sensitivity to Table 1 DSM-5 criteria for an addictive disorder (American Psychiatric Association, 2013) Criteria 1 The substance is often taken in larger amounts or over a longer period than was intended Criteria 2 There is a persistent desire or unsuccessful efforts to cut down or control use of the substance Criteria 3 A great deal of time is spent in activities necessary to obtain the substance, use the substance or recover from its effects Criteria 4 Craving or a strong desire or urge to use the substance Criteria 5 Recurrent use of the substance despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of its use Criteria 6 Continued use of the substance despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of its use Criteria 7 Important social, occupational, or recreational activities are given up or reduced because of use of the substance Criteria 8 Recurrent use of the substance in situations in which it is physically hazardous Criteria 9 Tolerance, as defined by either of the following: A. A need for markedly increased amounts of the substance to achieve intoxication or desired effect B. A markedly diminished effect with continued use of the same amount of the substance Criteria 10 Withdrawal, as manifested by either of the following: A. The characteristic withdrawal syndrome for other substance B. The substance (or a closely related substance) is taken to relieve or avoid withdrawal symptoms Bold text indicate criteria for an addictive disorder which are discussed in depth in the current manuscript with reference to their relevance to bulimia nervosa 260 Curr Addict Rep (2019) 6:258–265 sweet taste resulting from repeated bingeing on abstaining from salted food [49]. Furthermore, tiredness and hyperpalatable foods [27]. irritability have been cited as motivating factors for eating The development of impaired satiety mechanisms may be [45], providing some suggestion of food being used as a an indirect indicator of tolerance [6, 31, 32]. For example, a “pick-me-up”, or to avoid experiencing negative feelings recent functional MRI (fMRI) study found that women in stemming from withdrawal. remission from BN exhibited the same response to taste stim- Symptoms of psychological withdrawal are also widely uli in brain regions implicated in translating sensory informa- reported. Cross-sectional self-report accounts from patients tion about taste into motivated behaviour, regardless of wheth- with BN reveal that most feel tension, loneliness and physical er the individuals were hungry or sated, whilst healthy con- symptoms of anxiety before a binge, and the majority feel that trols showed an increased response to taste stimuli when hun- their negative psychological states are alleviated whilst en- gry versus when fed [33]. The authors also found an increased gaged in a binge [39� ]. Longitudinal studies using amygdala response in their remitted BN sample when fed Ecological Momentary Assessment technology also report compared to healthy controls, which they propose might pro- that binge eating and subsequent purging are usually preceded ject to the hypothalamus and motivate eating in the absence of by dysphoric mood states [50–52]. However, there is high hunger [33, 34]. It is possible that brain circuitry in BN fails to prevalence of depression and emotion dysregulation in BN de-value food reward when in a fed state, leading to eating populations [53], so it is not clear whether such presentations beyond metabolic need. of low mood represent psychological withdrawal from food. Five years on from Brewerton’s 2014 review, there remains Future research should aim to elucidate whether dysphoric a paucity of direct evidence of tolerance in humans in relation mood states before bingeing are distinct from more permanent to food intake and prospective, longitudinal studies are mood-related comorbidities, perhaps by comparing depressed needed. versus non-depressed individuals with BN. The first and only tool to evaluate withdrawal in the context Withdrawal Syndromes of addictive-like eating has been developed recently: the Highly Processed Food Withdrawal Scale—ProWS [39� ]. Preliminary evidence for a withdrawal syndrome in relation- This in part is derived from the premise that specific nutrition- ship to palatable food comes from animal models. There are al ingredients are capable of triggering addictive-like re- consistent observations of strong physical (e.g. forepaw trem- sponses [54]. In a pilot study, the ProWS was found to be or, teeth chattering) and psychological (e.g. aggression, anxi- positively associated with elevated YFAS symptoms, BMI ety) withdrawal responses in rats during periods of withdrawal and weight cycling in a community sample, and responses from sucrose [35–37]. The same observations, however, are on the ProWS explained an additional 11.2% of the variance not found with removal of high-fat foods [38] and have not yet in self-reported dieting success [39� ]. This tool may help dif- been studied with removal of highly processed foods [39� ]. ferentiate between the withdrawal effects from different types Neuroimaging studies show patterns consistent with this be- of palatable food [55, 56]. havioural data. Sugar-dependent rats show a significant in- crease in extracellular acetylcholine and a decrease in dopa- mine release in the nucleus accumbens shell, as compared to The Impact of Glucose Metabolism control groups, during a 36-h period of food deprivation [35], on Hedonic Eating Behaviour effects which are similar to withdrawal from morphine, nico- tine and alcohol. Preclinical Evidence Traditionally, withdrawal symptoms have not been clearly defined in the context of addictive-like eating, prompting crit- Sweet, pa latable foods act as unconditioned rewarding stimuli icism of the food addiction framework [40]. To date, the food in humans and rodent models, with evidence suggesting that addiction field has largely relied on observational and anec- merely tasting sucrose without digestion produces activation dotal clinical reports based on small cohorts or single case of dopaminergic circuits within the striatum [57]. However, studies [41–46] and on self-reported endorsement of with- there is evidence to suggest that palatable foods with a high drawal symptoms on the YFAS [18] and other withdrawal glycaemic index further contribute to the development of scales [47]. Cross-sectional self-report accounts are consistent compulsive binge eating behaviour through changes in dopa- in describing physiological symptoms of withdrawal similar minergic functioning triggered by wide swings in blood glu- to those experienced during opiate withdrawal [8, 48]. cose. One candidate mechanism for this effect relates to the Headaches, irritability and flu-like symptoms are reported by interaction between insulin and dopaminergic functioning. individuals abstaining from sugar [42], stomach pains, muscle The role of mesolimbic dopaminergic functioning in food spasms and shakiness by individuals abstaining or reducing approach behaviours has been reviewed extensively else- intake of carbohydrates [43, 45] and nausea by individuals where [58]. Dopamine-deficient mouse models exhibit severe Curr Addict Rep (2019) 6:258–265 261 aphagia leading to weight loss and death [59]. Conversely, the threshold for intracranial self-stimulation, thus indicating a stimulation of dopaminergic activity within the striatum trig- reduction of reward functioning. gers food consumption in rats without enhancing “liking” re- sponses (e.g. lip-licking and paw licking). Thus, dopaminergic Evidence in Humans functioning is thought to hold a role in food approach behav- iours (wanting) that is discrete from the hedonic response to Insulin resistance impacts on central dopaminergic systems in food receipt [60]. In contrast, central insulin suppresses feed- humans. For example, Dunn et al. [71] conducted a positron ing [61]. It is thought that the effects of central insulin and emission tomography (PET) study using the dopamine D2/D3 dopamine on food intake are not independent but rather inter- receptor radioligand [18F] fallypride and found that insulin act to regulate hedonic eating behaviour. sensitivity is negatively correlated with dopamine type 2 re- Dopaminergic neurons within the ventral tegmental area ceptor availability in the ventral striatum in a heterogeneous (VTA) express insulin receptors [62, 63], presenting a possible sample of lean and obese women. In men, Anthony et al. [72] mechanism by which insulin might influence the dopaminer- found that exogenously administered insulin increases metab- gic induction of feeding behaviour. Furthermore, central insu- olism in the ventral striatum and prefrontal cortex, whilst de- lin enhances the expression of dopamine transporter protein creasing metabolism in the right amygdala, hippocampus and within the VTA via a protein kinase B (Akt) signalling system cerebellar vermis. Furthermore, the effect of insulin in increas- [64, 65]. The enhanced expression of dopamine transporters ing metabolism in the ventral striatum and prefrontal cortex on the cell surface induced by insulin exposure is associated was lower in insulin-resistant versus insulin-sensitive partici- with greater dopamine uptake [66], thus reducing levels of pants [72]. This pattern of findings is thus indicative of trait- synaptic dopamine. level differences in the effects of central insulin on dopami- With regard to the effects of insulin on postsynaptic dopa- nergic mesolimbic regions, known to be critical for food crav- minergic signalling, in vitro studies have found that insulin ing and food approach behaviour [59, 73]. exposure invokes long-term depression of excitatory signal- Interactions between insulin resistance and central do- ling within VTA dopamine neurons extracted from male paminergic functioning may have functional significance C57BL/6J mice [67]. This effect appears to be long-lasting for food craving in humans. Chechlacz et al. [74], in an as, once induced, the long-term depression of VTA dopamine fMRI study, found that people with type II diabetes cells is not reversed by application of the insulin receptor mellitus (characterised by insulin resistance) exhibit great- antagonist S961 or through a tyrosine kinase inhibitor, which er blood oxygenated level dependent (BOLD) response to suppresses insulin receptor functioning [67]. food versus non-food images in the insula, orbitofrontal The effects of central insulin on dopaminergic functioning cortex (OFC) and basal ganglia, when compared to people within the VTA likely have downstream effects in suppressing without diabetes mellitus. Moreover, this increased activa- feeding and particularly hedonic feeding. For example, tion within the insula and OFC is positively correlated with Bruijnzeel et al. [68] found that injecting insulin directly into self-reported external eating. These findings, taken togeth- the VTA of female rats decreased 24-h food intake. Mebel er, thus provide evidence that insulin resistance, commonly et al. [69] have similarly found that injecting insulin directly observed following repeated excess consumption of fruc- into the VTA suppresses subsequent feeding in male C57BL/ tose in combination with an overall excessive energy in- 6J mice; however, this effect was dependent on the hunger take [75], is positively correlated with a pattern of neural status of the animals. That is, insulin in the VTA suppressed response to food stimuli which is associated with greater the quantity of sweetened high-fat food consumed by sated external cue-driven eating. However, it should be noted mice but did not affect normal chow intake in hungry mice. that the correlational nature of these findings limits the This pattern of effects therefore suggests that insulin activity ability to draw firm causal inferences. Although there is in the VTA acts selectively to suppress subsequent hedonic relatively less evidence regarding food craving in type I feeding, with weaker evidence for effects on homeostatic diabetes, an fMRI study has found that insulin detemir, feeding behaviour. which more readily enters the brain compared to standard Central insulin functioning may play a role in blocking the forms of insulin, is associated with reduced BOLD re- memory of palatable food reward or attenuating the incentive sponse to food images in the bilateral insula, a brain region salience of cues associated with palatable food. Evidence for associated with the regulation of appetite [76]. The authors this hypothesis comes from studies demonstrating that have speculated that insulin detemir may therefore induce a injecting insulin either into the cerebral ventricles [70]or more effective satiety reaction, thus explaining the reduced VTA [67] of rats at the time of memory retrieval reduces levels of weight gain observed in people with type I dia- conditioned place preference for palatable food. betes mellitus taking insulin detemir [77]. Furthermore, Bruijnzeel et al. [68] found that injecting insulin In a related study, Jastreboff et al. [78] recruited 25 men and at a dose of 0.005 mU/side into the VTA elevated the reward women in the obese weight range and 25 lean controls. 262 Curr Addict Rep (2019) 6:258–265 Fasting insulin and glucose were taken to measure insulin ventral striatum, whilst the opposite was observed in the resistance. During a subsequent fMRI task, audio scripts de- obese participant group [82]. Thus, there is evidence that signed to provoke relaxing imagery or favourite food imagery glucose impacts upon dopaminergic functioning separate- were played. Food craving was assessed before and after each ly from the effects of sweet taste alone, with BMI modu- imagery trial. The degree of food craving following food im- lating the direction of that effect. The reduced activation agery trials was positively associated with insulin resistance in stimulated by sugar consumption in obese participants is the obese, but not lean, participant group. Furthermore, the in line with previous evidence of downregulated striatal relationship between insulin resistance and food craving with- response to the receipt of sugar solutions, including choc- in the obese participant group was mediated by BOLD re- olate milk and milkshakes [83, 84]. sponses in dopaminergic regions including the VTA and There is a relative paucity of research investigating the substantia nigra. These studies suggest that insulin resistance effects of glucose metabolism on dopamine-mediated moderates craving and associated neural circuits in response feeding in BN and binge eating disorder without obesity. to food-related imagery. A recent meta-analysis of studies analysing insulin sensi- Thus, the above studies illustrate that interactions be- tivity in BN and binge eating disorders has found signif- tween central insulin and dopaminergic systems, known icantly reduced insulin sensitivity in both disorders [85��]. to impact on feeding behaviour in animals, also regulate Such insulin resistance therefore leads to greater flux in food craving in humans. Whilst this evidence therefore blood glucose following the consumption of foods with a supports a potential mechanism linking the short- and high glycaemic index, thus potentially contributing to long-term physiological effects of sugar consumption to food craving in a similar manner to that described above food craving in humans, it is also of interest to disentangle for populations with obesity [78]. The effect of insulin the effects of sweet taste on dopaminergic incentive sensi- resistance on glucose flux is further exacerbated by the tisation from the physiological effects of sugar in food wide swings in blood glucose induced by intermittent approach behaviour in humans. In support of the physio- fasting followed by objectively large binge eating epi- logical effects of glucose consumption on central dopami- sodes in people with BN [86]. Frank et al. [87] found nergic functioning, regardless of sweet taste, Haltia et al evidence of some trait differences in brain response to [79] found that the intravenous administration of glucose, glucose, with participants recovered from BN exhibiting versus placebo, was associated with increased D2 receptor suppressed BOLD response to a glucose, versus artificial binding potential in the right caudate nucleus and bilateral saliva solution, in the anterior cingulate cortex and left putamen in both lean and overweight women. However, cuneus in comparison to the control group. However, this intravenous glucose administration was rather associated study is confounded by the difference in sweet taste as well as nutritional content (glucose versus calorie-free with reductions in D2 receptor binding potential in the bilateral caudate nucleus, left putamen and right thalamus liquid). It will therefore be critical to carry out similar in men. It should be noted that the intravenous method of research to that described above for obesity in populations administration employed in this study bypassed the gastro- with bulimia-spectrum disorders in order to clarify the intestinal system, thus failing to stimulate the production of functional role of a glucose metabolism pathway in loss- gastrointestinal hormones, such as glucagon-like peptide 1, of-control binge eating versus the chronic overeating whichalsoimpactonappetitivefunctioning[80, 81]. This which commonly characterises overweight and obesity. study is therefore limited in the extent to which it directly bears upon the oral consumption of glucose versus calorie- free sweet taste. Nonetheless, these findings provide evi- Conclusion dence for the impact of glucose on mesolimbic dopaminer- gic functioning in the absence of sweet taste. The function- The current literature review has thus far served to illustrate al significance of the sexual dimorphism in brain response the existing state of the evidence with regard to food tolerance is not yet clear and would be an interesting avenue for and withdrawal effects in BN. Additionally, preclinical and future research. preliminary evidence in human studies has elucidated an In another PET study conducted in 19 participants with insulin-dependent mechanism whereby foods with a high BMIs ranging from the lean to obese weight range, dopa- glycaemic index interact with mesolimbic dopamine systems mine functioning was measured following the consump- and heighten food craving in cases of insulin dysregulation. tion of a 75-g oral glucose drink versus a calorie-free Nonetheless, there are several lines of evidence that should be sucralose drink of equal volume and sweetness. Within explored further before definite conclusions can be drawn the lean participant group, consuming the glucose drink, with regard to withdrawal and tolerance in BN and the phys- versus the calorie-free sucralose drink, was associated iological mechanisms which maintain addictive responses to with increased dopaminergic binding potential within the palatable food. Curr Addict Rep (2019) 6:258–265 263 Funding ML was supported by grants from the Swiss Fund for Anorexia 9. Murray S, Gordillo M, Avena NM. Animal models of eating disor- Nervosa. JT was supported by the National Institute for Health Research ders, substance use disorders, and addictions. In: Eating disorders, (NIHR) Mental Health Biomedical Research Centre at South London and addictions and substance use disorders. Berlin: Springer; 2014. p. Maudsley NHS Foundation Trust and King’s College London. 3–21. 10. Colantuoni C, et al. Excessive sugar intake alters binding to dopa- mine and mu-opioid receptors in the brain. 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Towards a Translational Approach to Food Addiction: Implications for Bulimia Nervosa

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Springer Journals
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Copyright © 2019 by The Author(s)
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Medicine & Public Health; Psychiatry; Neurology
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10.1007/s40429-019-00264-0
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Abstract

Purpose of Review In recent years, the food addiction hypothesis of loss-of-control eating has gained traction in the field of eating disorders. In particular, the neural process of food addiction plays a dominant role in the recently formulated “addictive appetite” model of bulimia nervosa and binge eating disorder. Nonetheless, several components of the food addiction hypothesis, including the presence of withdrawal and tolerance effects, as well as the proposition that some foods possess “addicting” properties, remain highly controversial. In response, the current review synthesises existing evidence for withdrawal and tolerance effects in people with bulimia nervosa. Recent Findings The recent development of a validated tool to measure withdrawal from highly processed foods will aid in measuring withdrawal symptoms and testing hypotheses related to withdrawal in the context of food addiction. We subsequently describe preclinical and human evidence for a central insulin- and dopamine-mediated pathway by which recurrent loss-of- control binge eating is maintained in bulimia nervosa. Summary Evidence in populations with bulimia nervosa and loss-of-control eating provides preliminary support for the role of food addiction in the maintenance of bulimia nervosa. Future longitudinal research is needed to develop a clearer profile of illness progression and to clarify the extent to which dysregulation in glucose metabolism contributes to food craving and symptom maintenance in bulimia nervosa. . . . . Keywords Food addiction Bulimia nervosa Eating disorders Sugar Dopamine Background In this article, we will use bulimia nervosa (BN) as the exem- plar. The “Addictive Appetite Model” proposes that three pri- The concept of “food addiction” has received increasing at- mary processes maintain psychopathology in BN: (1) the high tention in the scientific literature of recent years. While cogent salience of palatable foods [3], which is moderated by a ge- arguments have been made against the establishment of food netic susceptibility to food approach tendencies, reduced effi- addiction as a psychiatric diagnosis in its own right [1], there ciency in satiation processes [4] and/or episodes of food re- is substantial evidence to suggest that processes similar to striction; (2) chronic stress and interpersonal difficulties those observed in substance abuse disorders play a significant resulting in a deficiency of alternative rewards and a primed role in the maintenance of eating disorders in which loss of stress system [5]; and (3) large swings in blood glucose, control of eating is a feature (e.g. anorexia nervosa-binge caused by the consumption of foods with a high glycaemic purge type, bulimia nervosa and binge eating disorder) [2� ]. index, self-induced vomiting or insulin resistance (and insulin omission in diabetes mellitus). These pathways may contrib- ute to compulsive binge eating behaviour through aberrations This article is part of the Topical Collection on Food Addiction in dopaminergic function in a similar way to substance addictions. * Monica Leslie The current review presents a synthesis of the literature monica.leslie@kcl.ac.uk investigating some of the controversial aspects of applying the food addiction paradigm to eating disorders. For instance, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), there is uncertainty as to whether tolerance and withdrawal Section of Eating Disorders, King’s College London (KCL), 103 criteria for an addictive disorder as specified within the Denmark Hill, London SE5 8AF, UK Curr Addict Rep (2019) 6:258–265 259 DSM-5 are met. We also present a synthesis of molecular, consumption [13], a finding which may be of particular im- preclinical, clinical and neuroimaging evidence illustrating portance to BN as it is characterised by intermittent fasting how fluxes in glucose and insulin moderate central dopami- and binge episodes [14]. A similar downregulation of dopa- nergic functioning. mine D2 receptors is found in humans addicted to drugs of abuse [15] and is thought to be a key driver of compensatory overconsumption in the Reward Hyposensitivity Theory [16, Does Bulimia Nervosa Meet DSM-5 Criteria 17]. Behavioural observations in people with substance use for an Addictive Disorder? disorders mirror these findings. Individuals with BN endorse higher levels of tolerance-like The DSM-5 criteria for an addictive disorder are presented in symptoms measured using the Yale Food Addiction Scale (YFAS) [8], compared with healthy controls [18, 19]. There Table 1. The extent to which BN meets these criteria has been reviewed extensively elsewhere [6]. In his 2014 review, are clinical reports of subthreshold BN patients initiating larg- er and more frequent binge episodes over time [20]. Brewerton acknowledges significant phenotypic overlap be- tween disorders of substance dependence and BN but high- Consistent with these accounts is cross-sectional evidence of the correlation between higher body weight and frequency and lights a paucity of systematic clinical evidence for tolerance and withdrawal in the latter, a point frequently cited as a major severity of binge eating episodes [21]. Individuals with binge- weakness of the food addiction hypothesis [7]. Much research type eating disorders endorse significantly greater levels of on tolerance and withdrawal symptoms in humans to date has eating for purposes of reward enhancement compared with been largely anecdotal [8]. However, herein we synthesise the weight-matched controls [22]. Such evidence, although com- evidence from new assessment methods. pelling, remains indirect and is insufficient to prove the exis- tence of tolerance in humans. A preference for intensely sweet food and larger quan- Tolerance tities of sweeteners in individuals with BN is a character- istic often presented as an indicator of tolerance [3, The most compelling evidence for food tolerance is demon- strated in animal models, as previously reviewed by Murray 23–25]. Furthermore, this preference remains after ingesting a glucose load [26]. Magnetic resonance imag- et al. [9]. Rats who voluntarily overeat highly palatable food exhibit evidence of a neural reward deficit due to downregu- ing (MRI) studies indicate hypofunctioning of gustatory and limbic circuitry in BN patients when tasting palatable lated dopamine D2 receptors, which worsens as weight is gained [10–12]. This decreased sensitivity to reward is direct- food compared with controls [27, 28] and compared with individuals recovered from BN [29, 30]. This evidence is ly linked to the onset of compulsive food seeking in rats [11]. Repetitive bingeing on sucrose interspersed with periods of consistent with the idea that individuals with BN ingest dietary restriction causes rats to triple their overall daily sugar more food over time because of a decreased sensitivity to Table 1 DSM-5 criteria for an addictive disorder (American Psychiatric Association, 2013) Criteria 1 The substance is often taken in larger amounts or over a longer period than was intended Criteria 2 There is a persistent desire or unsuccessful efforts to cut down or control use of the substance Criteria 3 A great deal of time is spent in activities necessary to obtain the substance, use the substance or recover from its effects Criteria 4 Craving or a strong desire or urge to use the substance Criteria 5 Recurrent use of the substance despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of its use Criteria 6 Continued use of the substance despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of its use Criteria 7 Important social, occupational, or recreational activities are given up or reduced because of use of the substance Criteria 8 Recurrent use of the substance in situations in which it is physically hazardous Criteria 9 Tolerance, as defined by either of the following: A. A need for markedly increased amounts of the substance to achieve intoxication or desired effect B. A markedly diminished effect with continued use of the same amount of the substance Criteria 10 Withdrawal, as manifested by either of the following: A. The characteristic withdrawal syndrome for other substance B. The substance (or a closely related substance) is taken to relieve or avoid withdrawal symptoms Bold text indicate criteria for an addictive disorder which are discussed in depth in the current manuscript with reference to their relevance to bulimia nervosa 260 Curr Addict Rep (2019) 6:258–265 sweet taste resulting from repeated bingeing on abstaining from salted food [49]. Furthermore, tiredness and hyperpalatable foods [27]. irritability have been cited as motivating factors for eating The development of impaired satiety mechanisms may be [45], providing some suggestion of food being used as a an indirect indicator of tolerance [6, 31, 32]. For example, a “pick-me-up”, or to avoid experiencing negative feelings recent functional MRI (fMRI) study found that women in stemming from withdrawal. remission from BN exhibited the same response to taste stim- Symptoms of psychological withdrawal are also widely uli in brain regions implicated in translating sensory informa- reported. Cross-sectional self-report accounts from patients tion about taste into motivated behaviour, regardless of wheth- with BN reveal that most feel tension, loneliness and physical er the individuals were hungry or sated, whilst healthy con- symptoms of anxiety before a binge, and the majority feel that trols showed an increased response to taste stimuli when hun- their negative psychological states are alleviated whilst en- gry versus when fed [33]. The authors also found an increased gaged in a binge [39� ]. Longitudinal studies using amygdala response in their remitted BN sample when fed Ecological Momentary Assessment technology also report compared to healthy controls, which they propose might pro- that binge eating and subsequent purging are usually preceded ject to the hypothalamus and motivate eating in the absence of by dysphoric mood states [50–52]. However, there is high hunger [33, 34]. It is possible that brain circuitry in BN fails to prevalence of depression and emotion dysregulation in BN de-value food reward when in a fed state, leading to eating populations [53], so it is not clear whether such presentations beyond metabolic need. of low mood represent psychological withdrawal from food. Five years on from Brewerton’s 2014 review, there remains Future research should aim to elucidate whether dysphoric a paucity of direct evidence of tolerance in humans in relation mood states before bingeing are distinct from more permanent to food intake and prospective, longitudinal studies are mood-related comorbidities, perhaps by comparing depressed needed. versus non-depressed individuals with BN. The first and only tool to evaluate withdrawal in the context Withdrawal Syndromes of addictive-like eating has been developed recently: the Highly Processed Food Withdrawal Scale—ProWS [39� ]. Preliminary evidence for a withdrawal syndrome in relation- This in part is derived from the premise that specific nutrition- ship to palatable food comes from animal models. There are al ingredients are capable of triggering addictive-like re- consistent observations of strong physical (e.g. forepaw trem- sponses [54]. In a pilot study, the ProWS was found to be or, teeth chattering) and psychological (e.g. aggression, anxi- positively associated with elevated YFAS symptoms, BMI ety) withdrawal responses in rats during periods of withdrawal and weight cycling in a community sample, and responses from sucrose [35–37]. The same observations, however, are on the ProWS explained an additional 11.2% of the variance not found with removal of high-fat foods [38] and have not yet in self-reported dieting success [39� ]. This tool may help dif- been studied with removal of highly processed foods [39� ]. ferentiate between the withdrawal effects from different types Neuroimaging studies show patterns consistent with this be- of palatable food [55, 56]. havioural data. Sugar-dependent rats show a significant in- crease in extracellular acetylcholine and a decrease in dopa- mine release in the nucleus accumbens shell, as compared to The Impact of Glucose Metabolism control groups, during a 36-h period of food deprivation [35], on Hedonic Eating Behaviour effects which are similar to withdrawal from morphine, nico- tine and alcohol. Preclinical Evidence Traditionally, withdrawal symptoms have not been clearly defined in the context of addictive-like eating, prompting crit- Sweet, pa latable foods act as unconditioned rewarding stimuli icism of the food addiction framework [40]. To date, the food in humans and rodent models, with evidence suggesting that addiction field has largely relied on observational and anec- merely tasting sucrose without digestion produces activation dotal clinical reports based on small cohorts or single case of dopaminergic circuits within the striatum [57]. However, studies [41–46] and on self-reported endorsement of with- there is evidence to suggest that palatable foods with a high drawal symptoms on the YFAS [18] and other withdrawal glycaemic index further contribute to the development of scales [47]. Cross-sectional self-report accounts are consistent compulsive binge eating behaviour through changes in dopa- in describing physiological symptoms of withdrawal similar minergic functioning triggered by wide swings in blood glu- to those experienced during opiate withdrawal [8, 48]. cose. One candidate mechanism for this effect relates to the Headaches, irritability and flu-like symptoms are reported by interaction between insulin and dopaminergic functioning. individuals abstaining from sugar [42], stomach pains, muscle The role of mesolimbic dopaminergic functioning in food spasms and shakiness by individuals abstaining or reducing approach behaviours has been reviewed extensively else- intake of carbohydrates [43, 45] and nausea by individuals where [58]. Dopamine-deficient mouse models exhibit severe Curr Addict Rep (2019) 6:258–265 261 aphagia leading to weight loss and death [59]. Conversely, the threshold for intracranial self-stimulation, thus indicating a stimulation of dopaminergic activity within the striatum trig- reduction of reward functioning. gers food consumption in rats without enhancing “liking” re- sponses (e.g. lip-licking and paw licking). Thus, dopaminergic Evidence in Humans functioning is thought to hold a role in food approach behav- iours (wanting) that is discrete from the hedonic response to Insulin resistance impacts on central dopaminergic systems in food receipt [60]. In contrast, central insulin suppresses feed- humans. For example, Dunn et al. [71] conducted a positron ing [61]. It is thought that the effects of central insulin and emission tomography (PET) study using the dopamine D2/D3 dopamine on food intake are not independent but rather inter- receptor radioligand [18F] fallypride and found that insulin act to regulate hedonic eating behaviour. sensitivity is negatively correlated with dopamine type 2 re- Dopaminergic neurons within the ventral tegmental area ceptor availability in the ventral striatum in a heterogeneous (VTA) express insulin receptors [62, 63], presenting a possible sample of lean and obese women. In men, Anthony et al. [72] mechanism by which insulin might influence the dopaminer- found that exogenously administered insulin increases metab- gic induction of feeding behaviour. Furthermore, central insu- olism in the ventral striatum and prefrontal cortex, whilst de- lin enhances the expression of dopamine transporter protein creasing metabolism in the right amygdala, hippocampus and within the VTA via a protein kinase B (Akt) signalling system cerebellar vermis. Furthermore, the effect of insulin in increas- [64, 65]. The enhanced expression of dopamine transporters ing metabolism in the ventral striatum and prefrontal cortex on the cell surface induced by insulin exposure is associated was lower in insulin-resistant versus insulin-sensitive partici- with greater dopamine uptake [66], thus reducing levels of pants [72]. This pattern of findings is thus indicative of trait- synaptic dopamine. level differences in the effects of central insulin on dopami- With regard to the effects of insulin on postsynaptic dopa- nergic mesolimbic regions, known to be critical for food crav- minergic signalling, in vitro studies have found that insulin ing and food approach behaviour [59, 73]. exposure invokes long-term depression of excitatory signal- Interactions between insulin resistance and central do- ling within VTA dopamine neurons extracted from male paminergic functioning may have functional significance C57BL/6J mice [67]. This effect appears to be long-lasting for food craving in humans. Chechlacz et al. [74], in an as, once induced, the long-term depression of VTA dopamine fMRI study, found that people with type II diabetes cells is not reversed by application of the insulin receptor mellitus (characterised by insulin resistance) exhibit great- antagonist S961 or through a tyrosine kinase inhibitor, which er blood oxygenated level dependent (BOLD) response to suppresses insulin receptor functioning [67]. food versus non-food images in the insula, orbitofrontal The effects of central insulin on dopaminergic functioning cortex (OFC) and basal ganglia, when compared to people within the VTA likely have downstream effects in suppressing without diabetes mellitus. Moreover, this increased activa- feeding and particularly hedonic feeding. For example, tion within the insula and OFC is positively correlated with Bruijnzeel et al. [68] found that injecting insulin directly into self-reported external eating. These findings, taken togeth- the VTA of female rats decreased 24-h food intake. Mebel er, thus provide evidence that insulin resistance, commonly et al. [69] have similarly found that injecting insulin directly observed following repeated excess consumption of fruc- into the VTA suppresses subsequent feeding in male C57BL/ tose in combination with an overall excessive energy in- 6J mice; however, this effect was dependent on the hunger take [75], is positively correlated with a pattern of neural status of the animals. That is, insulin in the VTA suppressed response to food stimuli which is associated with greater the quantity of sweetened high-fat food consumed by sated external cue-driven eating. However, it should be noted mice but did not affect normal chow intake in hungry mice. that the correlational nature of these findings limits the This pattern of effects therefore suggests that insulin activity ability to draw firm causal inferences. Although there is in the VTA acts selectively to suppress subsequent hedonic relatively less evidence regarding food craving in type I feeding, with weaker evidence for effects on homeostatic diabetes, an fMRI study has found that insulin detemir, feeding behaviour. which more readily enters the brain compared to standard Central insulin functioning may play a role in blocking the forms of insulin, is associated with reduced BOLD re- memory of palatable food reward or attenuating the incentive sponse to food images in the bilateral insula, a brain region salience of cues associated with palatable food. Evidence for associated with the regulation of appetite [76]. The authors this hypothesis comes from studies demonstrating that have speculated that insulin detemir may therefore induce a injecting insulin either into the cerebral ventricles [70]or more effective satiety reaction, thus explaining the reduced VTA [67] of rats at the time of memory retrieval reduces levels of weight gain observed in people with type I dia- conditioned place preference for palatable food. betes mellitus taking insulin detemir [77]. Furthermore, Bruijnzeel et al. [68] found that injecting insulin In a related study, Jastreboff et al. [78] recruited 25 men and at a dose of 0.005 mU/side into the VTA elevated the reward women in the obese weight range and 25 lean controls. 262 Curr Addict Rep (2019) 6:258–265 Fasting insulin and glucose were taken to measure insulin ventral striatum, whilst the opposite was observed in the resistance. During a subsequent fMRI task, audio scripts de- obese participant group [82]. Thus, there is evidence that signed to provoke relaxing imagery or favourite food imagery glucose impacts upon dopaminergic functioning separate- were played. Food craving was assessed before and after each ly from the effects of sweet taste alone, with BMI modu- imagery trial. The degree of food craving following food im- lating the direction of that effect. The reduced activation agery trials was positively associated with insulin resistance in stimulated by sugar consumption in obese participants is the obese, but not lean, participant group. Furthermore, the in line with previous evidence of downregulated striatal relationship between insulin resistance and food craving with- response to the receipt of sugar solutions, including choc- in the obese participant group was mediated by BOLD re- olate milk and milkshakes [83, 84]. sponses in dopaminergic regions including the VTA and There is a relative paucity of research investigating the substantia nigra. These studies suggest that insulin resistance effects of glucose metabolism on dopamine-mediated moderates craving and associated neural circuits in response feeding in BN and binge eating disorder without obesity. to food-related imagery. A recent meta-analysis of studies analysing insulin sensi- Thus, the above studies illustrate that interactions be- tivity in BN and binge eating disorders has found signif- tween central insulin and dopaminergic systems, known icantly reduced insulin sensitivity in both disorders [85��]. to impact on feeding behaviour in animals, also regulate Such insulin resistance therefore leads to greater flux in food craving in humans. Whilst this evidence therefore blood glucose following the consumption of foods with a supports a potential mechanism linking the short- and high glycaemic index, thus potentially contributing to long-term physiological effects of sugar consumption to food craving in a similar manner to that described above food craving in humans, it is also of interest to disentangle for populations with obesity [78]. The effect of insulin the effects of sweet taste on dopaminergic incentive sensi- resistance on glucose flux is further exacerbated by the tisation from the physiological effects of sugar in food wide swings in blood glucose induced by intermittent approach behaviour in humans. In support of the physio- fasting followed by objectively large binge eating epi- logical effects of glucose consumption on central dopami- sodes in people with BN [86]. Frank et al. [87] found nergic functioning, regardless of sweet taste, Haltia et al evidence of some trait differences in brain response to [79] found that the intravenous administration of glucose, glucose, with participants recovered from BN exhibiting versus placebo, was associated with increased D2 receptor suppressed BOLD response to a glucose, versus artificial binding potential in the right caudate nucleus and bilateral saliva solution, in the anterior cingulate cortex and left putamen in both lean and overweight women. However, cuneus in comparison to the control group. However, this intravenous glucose administration was rather associated study is confounded by the difference in sweet taste as well as nutritional content (glucose versus calorie-free with reductions in D2 receptor binding potential in the bilateral caudate nucleus, left putamen and right thalamus liquid). It will therefore be critical to carry out similar in men. It should be noted that the intravenous method of research to that described above for obesity in populations administration employed in this study bypassed the gastro- with bulimia-spectrum disorders in order to clarify the intestinal system, thus failing to stimulate the production of functional role of a glucose metabolism pathway in loss- gastrointestinal hormones, such as glucagon-like peptide 1, of-control binge eating versus the chronic overeating whichalsoimpactonappetitivefunctioning[80, 81]. This which commonly characterises overweight and obesity. study is therefore limited in the extent to which it directly bears upon the oral consumption of glucose versus calorie- free sweet taste. Nonetheless, these findings provide evi- Conclusion dence for the impact of glucose on mesolimbic dopaminer- gic functioning in the absence of sweet taste. The function- The current literature review has thus far served to illustrate al significance of the sexual dimorphism in brain response the existing state of the evidence with regard to food tolerance is not yet clear and would be an interesting avenue for and withdrawal effects in BN. Additionally, preclinical and future research. preliminary evidence in human studies has elucidated an In another PET study conducted in 19 participants with insulin-dependent mechanism whereby foods with a high BMIs ranging from the lean to obese weight range, dopa- glycaemic index interact with mesolimbic dopamine systems mine functioning was measured following the consump- and heighten food craving in cases of insulin dysregulation. tion of a 75-g oral glucose drink versus a calorie-free Nonetheless, there are several lines of evidence that should be sucralose drink of equal volume and sweetness. Within explored further before definite conclusions can be drawn the lean participant group, consuming the glucose drink, with regard to withdrawal and tolerance in BN and the phys- versus the calorie-free sucralose drink, was associated iological mechanisms which maintain addictive responses to with increased dopaminergic binding potential within the palatable food. Curr Addict Rep (2019) 6:258–265 263 Funding ML was supported by grants from the Swiss Fund for Anorexia 9. Murray S, Gordillo M, Avena NM. Animal models of eating disor- Nervosa. JT was supported by the National Institute for Health Research ders, substance use disorders, and addictions. In: Eating disorders, (NIHR) Mental Health Biomedical Research Centre at South London and addictions and substance use disorders. Berlin: Springer; 2014. p. Maudsley NHS Foundation Trust and King’s College London. 3–21. 10. Colantuoni C, et al. Excessive sugar intake alters binding to dopa- mine and mu-opioid receptors in the brain. 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