The term obesity was paired with each of the following terms using the operator AND: food cues, food cravings, and reward-induced eating. The paired terms were used to perform a literature search on PubMed. Six human intervention trials investigating the effects of medications approved by the US Food and Drug Administration (FDA) for weight management on reward-induced eating and three human trials investigating the effect of a food-derived component on reward-related mechanisms were identified for the period ending August 31, 2016. Additionally, one medication-related trial Moldovan et al. was identified through a personal communication. The results of the PETAL study [
52,
53], a trial relating to food cravings, were presented at the meeting of the Obesity Society, 2015.
Pharmacologic Interventions
Anti-obesity medications are approved for individuals with a BMI of at least 30 kg/m
2 or a BMI of at least 27 kg/m
2 having at least one obesity-related co-morbidity. The combination of naltrexone extended release (ER) and bupropion ER (Contrave™) is approved by the FDA for long-term weight management in patients with obesity [
54]. Naltrexone and bupropion are approved by the FDA as monotherapies for other conditions. Bupropion, a dopamine reuptake inhibitor, is approved for the treatment of depression and seasonal affective disorder, and to aid in smoking cessation [
55,
56]; whereas, naltrexone, an opioid receptor antagonist, is approved for the treatment of alcohol and opioid dependence [
57,
58]. Bupropion is thought to stimulate secretion of α-MSH from POMC cells which produces an anorexic effect. Further, the antidepressant effects of bupropion and its effectiveness in aiding smoking cessation suggest that it mediates processes in the reward system [
59]. Although bupropion stimulates POMC activity, the anorexic effects of POMC are curtailed by the melanocortin system’s inherent feedback mechanism that limits sustained stimulation of POMC cells by simultaneous secretion of endogenous opioids such as β-endorphins that inhibit α-MSH secretion [
27].
Naltrexone monotherapy has little efficacy for weight management. However, consistent with the established role of opiates in the reward aspects of eating and stimulation of consumption of energy dense sugar and fat-laden foods [
60], naltrexone antagonism of opioid receptors reduces the subjective pleasantness or liking of certain foods [
61,
62]. Blockade of the µ-opioid receptor with naltrexone to counteract the auto-inhibitory actions of bupropion-stimulated release of endogenous opioids forms the basis of the combination treatment of bupropion and naltrexone for obesity treatment. Moreover, naltrexone and bupropion both reduce food intake in mice when injected directly into the reward system; but the effect is synergistic when they are administered together. Results from the phase III trials showed that the combination treatment of naltrexone and bupropion consistently reduced measures of food reward assessed using the COEQ [
43,
44,
63]. Subjects reported reduced frequency and strength of food cravings (Table
1).
Table 1
Therapies for reducing reward-related eating
Naltrexone + bupropion (Contrave™) | Reduces frequency and strength of food cravings | |
Phentermine (Adipex-P™, Ionamin™)a
| Suppresses appetite | |
Lorcaserin (Belviq™) | Improves facets of inhibitory control | |
Lorcaserin + phentermine | Reduces frequency and strength of food cravings. Reduces cravings for high-fat foods, sweets, fast foods | |
Liraglutide (Saxenda™) | Reduces attention to food cues | |
Thylakoid membranes (Appethyl™) | Reduces desire for sweet foods and chocolate | |
Phentermine (common brand names Adipex-P™, Ionamin™) is primarily a noradrenergic and perhaps dopaminergic sympathomimetic amine that acts as an appetite suppressant [
64]. It was approved by the FDA for use in conjunction with lifestyle change efforts for short-term (few weeks) weight management [
65]. A 12-week randomized controlled trial evaluated the effect of phentermine and a meal replacement system along with nutritional counseling on weight loss and food cravings. A greater proportion of subjects in the phentermine group achieved weight loss of 5% or more, and the craving for fats and sweets (evaluated using the Trait and State Food Cravings Questionnaires) was reduced in the phentermine group, compared to the group receiving the meal replacement and counseling along with a placebo. Further, the reduction in craving positively correlated with weight loss over the 12-week period [
66].
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that regulates food intake and energy expenditure by acting on the central nervous system, with the key mediators being the 5-HT
2C receptors (5-HT2CR) [
67]. Agonists of 5-HT2CR activate POMC neurons which results in the release of α-MSH and activation of the anorexigenic central melanocortin pathway through MC-4R [
68‐
70]. Lorcaserin (Belviq™) is a highly specific 5-HT2CR approved by the FDA for the long-term treatment of obesity [
71]. Studies showed that lorcaserin produced weight loss without the adverse cardiac outcomes associated with non-specific serotonin receptor agonists [
72‐
74]. The role of 5-HT2CR in the regulation of forebrain dopaminergic systems is well established [
75‐
77], suggesting that agonists of 5-HT2CR should affect behaviors motivated by food [
78]. On the basis of research in substance abuse, it appears that agonists of 5-HT2CR including lorcaserin improve facets of inhibitory control, which has the potential to prevent relapse following a period of abstinence [
78‐
81]. Given the neurobiological and behavioral commonalities between obesity and drug addiction, it is not surprising that lorcaserin has been investigated for its effects on food cravings.
In the Pilot Evaluation of Tolerability and Safety of Lorcaserin and phentermine (PETAL) study, conducted to evaluate if administration of the combination of lorcaserin with immediate release phentermine for 12 weeks was associated with adverse events, the effect of the drug administration on food cravings was also evaluated as a secondary endpoint. Subjects were given lorcaserin 10 mg twice daily or lorcaserin 10 mg twice + phentermine 15 mg once daily, or lorcaserin 10 mg twice + phentermine 15 mg twice daily. Weight loss at 12 weeks was 3.3%, 6.7%, and 7.2% in the lorcaserin only and the combination with phentermine once or twice daily, respectively.
Analysis of the food craving data evaluated using the FCI indicated that subjects in all treatment groups showed improvement in the FCI total score from baseline to week 12 as well as in the FCI subscale scores for high-fat foods, sweets, carbohydrates, and fast foods without any one particular category of foods driving the overall effect [
52]. Subjects also reported improvements in control of eating in all treatment groups at week 12 compared to baseline, evaluated using the COEQ. The frequency and strength of food cravings reduced including the craving for chocolate, sweets, non-sweets, and starchy foods in a sample that comprised 85% women. The limitation of this study is that there was no placebo-treated group [
53].
In the brains of humans GLP-1 receptors have been identified in the hypothalamus, medulla, and parietal cortex [
82]. In human subjects, the GLP-1 receptor agonist exenatide reduced activation in response to food cues in brain areas involved in the regulation of reward, the effect of which was greatly attenuated by GLP-1 receptor blockade [
83,
84]. The response to GLP-1 receptor blockade was more pronounced in subjects with type 2 diabetes and obesity than in lean healthy subjects [
85]. In response to treatment for 17 days with liraglutide (Saxenda™) a GLP-1 agonist approved by the FDA for long-treatment of obesity [
86], activity in the parietal cortex decreased when subjects viewed images of highly desirable foods compared to placebo. The parietal cortex is involved in controlling the location of attention [
87]; hence, it is likely that there was a reduced appeal of the food cues, especially since liraglutide treatment also increased fullness and reduced food intake [
82]. However, gastric inhibitory peptide increased and serum leptin decreased in response to food cues, each of which has opposing effects in the areas of the brain involved with reward mechanisms [
88]. Leptin is secreted by fat cells and binds to specific leptin receptors on dopaminergic neurons in the ventral tegmental area to inhibit dopamine signaling in the nucleus acumbens and amygdala. Unlike gastric inhibitory peptide, leptin reduces reward-related eating behavior [
89]. The short-term effects of liraglutide on reward mechanisms warrant corroboration in future studies.
Food-Based Interventions
Thylakoids are compartments inside the chloroplasts of green plants such as spinach and are composed of membranes that form the internal photosynthetic membrane system of chloroplasts. By interacting with lipids and delaying fat digestion, thylakoid membranes promote the release of hormones that mediate satiety [
90]. Studies investigating the effects of thylakoids (Appethyl™) on eating behavior have demonstrated increases in perceptions of satiety [
91,
92], and a reduction in body weight [
93]. Additionally, two studies demonstrated a decrease in the craving for sweet foods and chocolate among women in the overweight or obese body mass index range, measured subjectively [
93,
94]. In another study, men tended to reduce their intake at a pizza meal; whereas, among women food intake did not change following a 5-g dose of thylakoids [
91]. Men and women tend to crave different kinds of foods, have different experiences of craving, and differ in their responses. Men report a craving for savory foods, and a disproportionately large percentage of those who experience a craving for chocolate are women [
29]. The gender differences demonstrated by studies investigating the effects of thylakoids suggest that thylakoids may influence the reward system.