Hi, everyone. Good morning. Thank you so much for joining us here, bright and early, it feels like, on this beautiful San Francisco day. I'm Dr. Ashley Gerhart. I'm a professor of psychology at the University of Michigan. And we're here today to speak with you about the idea of whether there is a new substance use disorder surrounding food intake. The first thing I just wanted to give everyone one last moment to do is we're starting off today's talk with a quick survey, quick gut check of the audience. And you can answer this poll if you would like. I'll give it just one more moment here. You can do that by either going to PollEV.com, and there's a backslash AshleyGerhart757, and you can enter A or B to cast your vote for whether highly rewarding foods can trigger addictive processes. A is yes, B is no. You can also text AshleyGerhart757. That would be kind of like where the number would go. Or you text that to 37607. And then once you join, you can use A or B. So I'll give that just a moment for anyone who would like to enter the survey anonymously. We'll get results, and then I'll do a brief introduction. OK, so we might be a slightly biased sample since you all decided to get up early and come visit us. But we're seeing that thus far our audience thinks that this is a valid construct that may be feasible and plausible. So we'll be looking forward to discussing that with you more now and presenting some science on that. Excellent. So as I mentioned, I'm Dr. Ashley Gerhart from the University of Michigan. And I'm going to be giving a very brief introduction to this topic today. And then we have three different talks and a discussant. And then we'll actually hold all the questions after the talk to a panel Q&A at the end where everyone will be able to kind of answer questions. So I'm going to start with a little bit of background on what we're going to be talking about. So a panel Q&A at the end where everyone will be able to kind of ask us their questions as they please. But we'll be holding questions between talks just due to time. So a disclosure slide for me as I have no relevant financial relationships to disclose. And I often like to start talks in this frame with this idea of whether certain foods could be addictive by taking a step back and thinking about how we create any sort of addictive substance. Addictive substances don't typically occur in a natural form. There's no wine river or a tree that just has joints on it. What we do is we take naturally occurring substances, we refine them, and we process them into more activating and rewarding profiles. And then that can cause difficulties for some people. And so an example I give is tobacco. This is a picture of a tobacco leaf. It has nicotine in it, which is a psychoactive substance. But people really don't consume the straight tobacco leaf. It really is a result of drying and curing, refining and processing that tobacco leaf, and then setting it up in a delivery system where you can roll it and smoke it, that you get high levels of nicotine, unnaturally high levels of nicotine, delivered rapidly to the brain. And in this context, this tobacco leaf went from something that people don't usually consume that often to something that people can get addicted to. But really what we've seen is that as our technology advances, the substances and the environment surrounding those substances play a key role. So while tobacco has been a part of human culture and history and different religious societies for a long time, we really didn't see widespread cigarette smoking until the late 1800s, when the industrialized cigarette roller came into existence. And suddenly it went from having to hand roll a cigarette where you could get a few a minute to these industrialized cigarette rollers where you could get thousands of cigarettes just quickly produced very rapidly. And so there became an opportunity for kind of big business and people to make a lot of money off these quick and easy to make cigarettes. But the cigarettes that were sold weren't just pure, dried, cured tobacco. They were ultra-processed cigarettes with thousands of different additives that really enhanced the magnitude and addictive nature of the nicotine itself. And a lot of these additives are actually around the taste and the flavor profile of the cigarette. Things like menthol and sugar and cocoa are some of the number one additives for tobacco. And as we saw that these new ultra-processed, cheap, easily accessible, heavily marketed tobacco products became flooding the market, we saw an over 1000% increase in cigarette smoking and we saw a global epidemic of diseases that were associated with increased tobacco intake. I find that that story shares some really compelling parallels with how we've changed our food environment. You know, the reward and motivation systems that the cigarette uses to activate a desire for motivation, to compel use, are reward and motivation systems that were really shaped by humans' needs for calories and the fact that famine was always such a threat that there's evidence that we, our brains are more responsive. We get more of a reward response. We're more sensitive to cues and experience craving for foods that have taste and flavor profiles that suggest that they're calorie dense. Things like the sugar in plants or the fat that's in meats or nuts. But again, through technology, we've gotten very good at stripping out the rewarding, reinforcing ingredients in that fruit and that nut and being able to create processed and refined straight versions of sugar, of fats that people could buy and purchase and create homemade cookies and homemade breads and make these products more affordably at home. But what seems to have really triggered the time period where there's been this massive increase in obesity and diet-related disease is industrial ultra-processed versions of products that now flood our market and make over 60% of the American diet are foods that have unnaturally intensely high levels of refined carbohydrates, fats, augmented by flavor enhancers and additives that allow them to be shelf-stable, particularly flavorable, heavily marketed and cheap. And as we've seen since about the late 1970s and 80s when our food environment started to change so rapidly, as we've seen an increase in things like binge eating, obesity, diet-related disease, which leads to some to question, is it possible that these highly rewarding processed foods have maybe triggered, have hit the scales strong enough that for at least some people, they can trigger that addictive, compulsive behavior? And the parallels really don't end there. When we look at the 1970s and 1980s, is really a time that Philip Morris, R.J. Reynolds tobacco companies diversified their portfolios by buying up food companies like General Mill and Kraft. And we've seen that this great work that's been happening here at UCSF by Laura Schmidt's lab has been finding that in that time, tobacco took their playbook and their know-how of how to sell and market and flavor cigarettes and applied that to their foods and targeted children and targeted racial ethnic communities, used flavors and additives from their cigarettes and transferred them to their food portfolio. And tobacco was, Big Tobacco was the biggest creator and producer of processed foods through about the mid 2000s when they divested of many of their food companies, although they still play a role with many foods. So really the parallels between both the creation and the companies that are playing a role in those sorts of foods that are now dominating our food environment have a lot of parallels. And one of the concerning factors that we see is as these ultra processed, highly rewarding foods start to dominate the food environment, we see that they replace nourishing, minimally processed foods that have taken up that used to be kind of the bread and butter of the human diet, things like fruits, vegetables, legumes. As these ultra processed foods become more and more available, people eat more of those and they eat less fruits, vegetables, beans and other nourishing foods. And this is happening despite greater and greater knowledge about the health consequences of high sugar, high fat, high ultra processed foods. We now see that people are dying of preventable deaths related to poor diet at a level that surpasses alcohol and is really starting to be on par with tobacco. And we have a $30 billion diet industry that exists to try and help people eat less and lose weight. And we find that really most of these diets don't appear to work in a sustainable longterm way with most people lapsing back to their prior patterns of intake. So all of these environmental changes have led to some overarching questions, some of which we're hoping to talk about today. Can highly processed foods trigger addictive mechanisms that contribute to overeating and obesity? Are some people experiencing a clinically significant addiction to highly processed foods and should a highly processed food substance use disorder be in the DSM-5? The outline for today's session is the following. I'm not gonna go into detail about all the qualifications of our speakers because I could literally do that for the entire hour I'm here today. But we have Dr. Jinjia Guang from the Lab of Neuroimaging Director at the National Institute of Alcoholism and Alcohol Abuse. He'll be speaking with you about the role of reward dysfunction and overeating of high calorie foods and obesity. Then we'll next have Dr. George Koob, who's the Director of NIAAA. He'll be speaking with us about hyperkatifeia and negative reinforcement as a driving force in addiction like overeating. Finally, I'll come back up and speak to you about some of my work on evidence of a highly processed food substance use disorder. Then we'll have Nora Volkow come up and who's the Director of the National Institute of Drug Abuse. She'll be the discussant for today's panel. And so she'll provide you with her reactions and an overview. After that, I'll take another survey about people's attitudes and thoughts about this topic. And then we'll do a Q&A with our panel to finish up today so we have an opportunity to speak with us all. So next, I will ask Dr. Wang to come up and start his talk for us. Thank you for joining us. Thank you. Good morning, and thanks, Ashley, in my to have this interesting talk. I would like to share my experience on obesity using imaging method. There is no study supported by that government, and we have no relevant financial relations to this course. Just a few months ago, we published an article to review all that article published in the journals to study obesity, and it was a structure, a functional MRI, and this is the result of our review published in Molecular Psychiatry. We found that obesity is associated with abnormality of the frontal mesolimbic circuitry and impaired cognitive functions. If you are interested, you can read this article. One of the articles inside, we found that by using that racing state functional connectivity, we found that obese person, they have this altered brain function, and that they might contribute to their higher craving for food and a greater perception of hunger and a lack of control over eating. And in my talk, I will discuss obesity is associated with brain changes, including stronger brain response to food cues and more food craving, lack of control of overeating, compulsive overeating, and increased perception of hunger and impaired memory of how much you eat. And overeating behavior in people with obesity is very similar to compulsive drug use in people with substance use disorder. And compulsive behavior in obesity and substance use disorder relate to the dopamine system. And many years ago, when Dr. Volkow and I, we studied a substance use disorder such as cocaine, meth, amphetamine, alcohol, even heroin, we found that the person with a substance use disorder has a low dopamine D2 receptor. About in the late 1990s and early 2000, we published an article. We've shown that the compulsive eating behavior in obese subject, they have a very similar dopamine D2 decrease compared to the control subjects. And after this study, we tried to understand how did that happen. So we have a list of the study. We tried to understand our finding. And the first is using that food stimulation. That means that we present the food that the subject, they prefer, and then we give them 10 items and then see how their brain responds. And we found that during the food presentation, and the people can smell and taste, but without eating, that a person show dopamine release, and that is more of the dopamine release relate to the desire for food. And then we use another method to try to understand how it relate to the brain functions by using radioactive sugar, using that FDG and post-traumatic emission tomography. We found that many area of the brain activated, especially in our somatosensory cortex area. And also we found a very interesting is that the increase in the orbital frontal cortex. We found that in this OFC, that increase the greater the activation, also with higher feeling of hunger. Since that the orbital frontal cortex is regulated by dopamine activity, is a key brain region for controlling and planning behaviors. It also determined the present and the probability of food. The enhance of the orbital frontal cortex activation by the food stimulation are likely to reflect downstream dopaminergic effect and likely to participate in dopamine's involvement in drive for food consumption. And laterally, we want to understand, can this activation be suppressed by asking the person to suppress their desire to eat during the food stimulation? We use the same food stimulation by asking the people who they like. In another extra study, we asked the person to suppress their desire for food. And even we give them all this food in front of them, they have to suppress their mind and to ignore all this stimulation. We found that for the male subject, they did decrease their feeling of the hunger. And we also found that it reflect into the FDG study that the person decreased in many region of the brain. As you can see in the images that with a blue area, the location decreased during the suppression of their desire. Those are the area related to the food craving and motivation to eat and satiety and memory. And later on, we use that MRI to study that to compare that normal weight, overweight, and obese person by using MRI technology with food paradigm that compare with high-calorie food, low-calorie food, and a controlled substance, the control. Those are non-food items. And we found that compared to obese and overweight and normal weight person, the obese group had both greater basal activity and food cue-induced activation than the overweight and normal weight group. That is especially in the amygdala and hippocampal area. And when we compare to their body weight index in this resting state and the food cue study, we found that obese group are both resting in that amygdala, hippocampal activity, and the high-calorie food cue-induced response were correlated with that body mass index, but not in the other two group. And so we want to see this mediation effect. We found that this mediation effect is that the relation between the body mass index and the left hippocampal amygdala area responses to the high-calorie food cue can be mediated by their resting activity. Then we try to see if obese person, when we ask them to suppress their desire to eat, can that be different from the normal weight person or not. Very interesting is that we found that non-obese has a significant increase in that from the baseline to the food stimulation state, and the decrease as we ask them to do it, and it decreased from that food stimulation to attempt inhibition. And obese has that increase, decrease from the baseline to food stimulation, and the increase from that food stimulation to the attempt inhibition in the glucose metabolic area of the same regions. And then it's very interesting is that one location, particular in the area called anterior cingulate cortex, that is Bowman area 32, people also call that is medial ventral prefrontal cortex. And in that area is that the obese person, they cannot suppress this area as it happened in that non-obese person. And then we compare to their desire, and then we find that in the non-obese subject had less desire for food during the attempt, the cocaine inhibition, that was associated with that less activation in the BA32. And this is consistent with that non-obese subject show less activation in this cluster during attempt inhibition than food stimulation. And later on, we also use another method called delayed discount test that by asking the subject during the scan, and we say that, would you rather to have like 20 Chinese dollar now or you want to have the 100 Chinese dollar in two weeks? And then the feedback, you select that like 100 Chinese dollar in two weeks or those kind of things. Then it's very interesting that we find that this is the method to see whether that impulsivity issue. And then we find that the subject with obesity prefer eat right away rather than waiting. For them, eating is a bigger reward than exercising is. And as Dr. Volkow in our group, we published this how the addictive dimension in the obesity, and we find that this how we eat is affected by what our brain tells us. So we also ask ourselves, could it be also what we, our gut tells us? So we use that bariatric surgery as our model to understand the gut and brain interaction. One of our collaborators in China, they receive, have the tons of that obese person receive that periscope sleep gastrectomy, and that is a surgery remove the larger part of main stomach region that producing grayling is called larger curvature. And grayling is a stimulus that dopamine release from that ventral tegmental area. And it is the only hormone outside the brain that makes you feel hunger. And we find that during our follow-up, all these patient receive that bariatric surgery, their bodymax index decrease, and then that is gradually down to 12 months. And then also their food craving also decrease. So bariatric surgery cause this reduction in bodymax index and the craving for high calorie food. So in the sixth month after the surgery, we did the study to see how the brain responds to the food cue. We found that the person has that decreased area of the dorsolateral prefrontal cortex area. That is area related to that, our inhibition control. And very interesting is that these changes in that DL-PFC also correlate with the area in that medial prefrontal cortex. That is in the, we call ventral ACC, the area exactly that there was issue in the obese subject when we asked them to suppress their desire for food, and they have issue in that area. And that is area related to the food craving. So in other words, that the lower grading level, which improve the brain control your eating behavior, also has ability more easily to suppress urge to eat high-calorie foods. And a year later, when we follow up, the patient received the surgery. We found that one area popped up, and that is area in that thalampic area, medial dorsal thalampic area, and also is area called habendiora. They are very close to each other. Habendiora is a region related to our negative emotionality, and people call that anti-reward area. And that improve the connectivity in the habendiora. And then also, we found that the enhance of the connectivity, it reach into the area related to that hedonic and also homeostasis area. And that these stronger connections in the brain that make a person have a stronger brain system when a person feel depressed. And that means that they have less emotional and mindless eating. So the take-home message from my talk is that obesity is associated with brain changes that make it harder to control craving and overeating. Those brain changes can be reversed through the lifestyle changes, including exercise and mindful eating. More research on gut and brain interaction can treat and prevent overeating. I would like to thank you for listening, attention, and I also like to thank my colleagues when I was in Brookhaven National Laboratory, and our group in Bethesda, Laboratory of Immune Genes, and my collaborator in CN China. Thank you very much. Thank you, Jean-Jacques. As I mentioned, we'll be holding questions until the end, and I'm going to pull up Dr. Koob's talk. Well, it's a pleasure to be here, and I'm glad there's so much interest in this topic. It really is an important one. I just want to make one point out from this slide, and that is that I work in the intramural research program at NIDA, and I think you figured out that Nora works in the intramural research program at NIAAA. But we both work together and have done for many, many years. But I'm not going to really focus on that work today. What I'm going to do is more a conceptual talk, fill in the blanks, I think, to some extent on how you link what Jean-Jacques just talked about, which is highly relevant to processed foods and, you know, an addiction like overeating. But I'm going to talk about what we loosely call the dark side of the addiction process, or the negative emotional side of the addiction process. So I'm going to give you a very brief overview of the neurocircuitry of addiction, hyperkatifeia, a word I made up, I'll tell you about that, opponent process, and negative reinforcement, and just touch on the neurobiological basis of hyperkatifeia, within and between system neuroadaptation, some of which Jean-Jacques just alluded to, and then evidence of hyperkatifeia in animals and humans in food addiction, and shifts from palatable food to non-palatable food produce hyperkatifeia, both in humans and animals. And then just touch on some of the work we did with a number of K99s and my postdoctoral fellows at Scripps Research that is, I think, still relevant to the topic today. So how do I define addiction? Well, like everybody else, compulsion to seek and take drugs or stimulus, in this case highly processed foods or very palatable foods, loss of control and limiting intake. And I add on the emergence of a negative emotional state, dysphoria, anxiety, irritability, when access to the drug or stimulus is prevented. You've seen the three-state cycle. This has evolved. Nora and I have published extensively on this. Actually, we formed this cycle based on me teaching undergraduates at the University of California in 1997, and I talked about that yesterday in one of the alcohol symposiums. But the three stages have held up and now been validated by quite a few studies using factor analysis of large groups of patients, and they not only have construct validity but also now, in some of the studies, predictive validity. And so the binge intoxication stage encodes the domain of incentive salience and pathological habits. The withdrawal negative affect stage encodes reward deficits and stress surfeit. And as you just heard, the preoccupation anticipation stage or the craving stage encodes executive function deficits. And they're color-coded here if you're anatomically, neuroanatomically challenged. So the basal ganglia for the binge intoxication stage, the extended amygdala, and you'll see the same habenulon there that Gene Jack was talking about in the negative affect stage. And then you can see here that the preoccupation anticipation stage is largely prefrontal cortex and allocortex, old cortex. So how did I get into this part of the addiction cycle? Well, I like to say that I spent the first half of my career trying to understand how we feel good. And as I get older, I'm trying to spend the last half of my career trying to figure out how we feel bad, all right? And it's all predicated on an old story and hypothesis by Richard Solomon at the University of Pennsylvania. And, you know, in the simple terms, it's hedonically, hedonically what goes up must come down. And or as I say, there's no free ride in the brain, all right? So think about that. The real title of this slide is Standard Pattern of Effective Dynamics Produced by Novel and Repeated Unconditioned Stimulus. It's a really fantastic paper. And basically, the argument is this is an A process where we feel good, the hedonic positive effects of a drug or food. And there's a B process where we feel bad. And the argument is as we become more and more involved in the compulsive aspects of whatever drug or food issue that we're talking about, the B process gets bigger. And some would argue that the B process actually gets so large that it subtracts out the A process and we call that tolerance. And I'm not going to spend much more time on this, but I've been obsessed with what causes the B process. And I might point out to you that a B process occurs in normal life. I mean, you might get some huge award and the next day you're a little bit down and you recover, hopefully. And that's part of the way our brain reacts to over activation of the reward system, simply. There's payback. So I got tired of writing hypersensitivity to a negative emotional state. And the word dark side didn't really convey what I wanted to say as well. So I decided to make up a word. And I asked my brother, Steve, who's an archeologist conservator, speaks Greek fluently, for a word in Greek for dejection, sadness, or negative emotional state. And I had in the back of my mind hyperalgesia, which all of you know what that is, increased hypersensitivity to pain, which also occurs during withdrawal from most drugs of addiction. And so I put hyper in front of catephia, and it's defined as the increased intensity of negative emotional motivational symptoms and signs observed during withdrawal from drugs of addiction. But you can, in the context of my talk today, think of this in terms of highly palatable foods, withdrawal from highly palatable foods. Hypercatephia is hypothesized to represent elements such as dysphoria, irritability, alexithymia. I don't have to explain that to this audience. Symptoms simply often described as ill at ease, uncomfortable within one's own skin, or simply not hedonically normal. Symptoms historically difficult to define. I want to point out to you, you know, this is not major depressive episodes, okay? I'm talking about something below that line, somewhere where you're not tiptoeing through the tulips, but you're not also at a level where you, as psychiatrists, would prescribe, you know, a serotonin-selective reuptake inhibitor. So how do I put this all together? This is really, in some sense, the summary of my talk here. So the progressive outcome with repeated exposure to the highly rewarding palatable food is predominance of the opponent process, which I just explained to you. Consequently, a greater quantity and more frequent use of the previously rewarding food are needed to maintain or approach euthymia, normal mood state. When the substance is not used, then negative emotional signs of withdrawal emerge, including irritability, anxiety, dysphoria, and subjective feelings of need. This deficit emotional state, or hypercatephia, is proposed to be dissociable from the somatic signs of withdrawal. Actually, that's a big point, and I'm not going to dwell on it, but I don't believe the somatic signs of withdrawal are hypercatephia. Sometimes they contribute to it. If you're writhing in pain with your gut completely dysfunctional during opiate withdrawal, it certainly contributes to hypercatephia, okay? And so these negative emotional states sensitize and become persistent with repeated use. As a result, hypercatephia may be seen, despite months of sustained abstinence, under this conceptualization, food intake is compulsively escalated or reinstated in relapse via negative reinforcement mechanisms. And I want to remind you that negative reinforcement is the removal of an aversive stimulus causes the increase in behavior, okay? It's not punishment. Punishment is where you suppress behavior by administering a stimulus. As a result, so under this conceptualization, food intake is compulsively escalated via negative reinforcement mechanisms because it transcendently prevents or relieves the negative emotional symptoms. Reinstatement of substance use is ultimately self-defeating, however, because it perpetuates the vicious opponent process cycle. And ultimately, my argument is, this is really important to me, this point. You end up taking the substance to fix the problem that the substance itself caused. And so this is a slide that Larry Parsons put together. He passed away very early in his career, but I liked it so much that I asked him whether I could borrow it. And the argument is, yes, reward plays a key role in addiction, no question, but also relief plays a key role in addiction. And you can loop back into the cycle via the preoccupation anticipation stage. You notice I'm still color-coded here. And you can loop back to the reward part or you can loop back to the relief part. I'm focusing on the relief part today. And then, you know, a long, long time ago, Floyd Bloom and I hypothesized that in addiction there were two types of neuroadaptations. One was within system and one was between system. And without reading the slide, in the interest of time, I'll just say, think dopamine for a within system neuroadaptation. Nora Volkow and her team have published a myriad of papers, as many other labs now, showing that dopamine system is compromised during withdrawal. But there's other things that are occurring during withdrawal, and one of them that I've spent most of my career now, latter part of my career working on, is the activation of the brain stress systems. The activation of the brain, in a sense, anti-reward systems. And so here's one conceptualization that the basal ganglia system that includes our reward and incentive salience and by some pathological habits is actually compromised when you stop taking palatable foods. And so this is the darkened part here is the famous mesolimbic dopamine system projecting to the nucleus accumbens, opioid peptides interacting at both ends of the mesolimbic dopamine system. And I stole this from Eric Nestler many years ago, but I should actually probably attribute it to him on there, but it's one of my favorite slides. But one that we conceptualized at the Scripps Research Institute, even before I came to the NIH, was that there's another major system, which we call the extended amygdala. And you can see it in red here, it includes the central nucleus of the amygdala, but also the shell of the nucleus accumbens, bed nucleus stria terminalis. And there are literally almost 10 different neurotransmitter systems that activate the extended amygdala, which is known to be critical for fight or flight, for mediating hyperkinephia, to be honest with you. And there are also buffer systems, like the antistress systems you may have heard about, like endocannabinoids, the endogenous cannabinoid system, oxytocin, neuropeptide Y, nociceptin. What is the evidence that there is actually negative affect or hyperkinephia, as I would call it, during abstinence from palatable food in humans? Well, I just went through the literature and caught up a little bit on some of the studies that we had outlined a number of years ago. Severe binge eating is mediated by the relationship between negative emotional symptoms and food addiction, Imperatori et al. Switching to a lower-fat diet increased anger, anxiety, and hostility during the next month, Wells et al. Hunger increases smoking relapse and is considered a relapse trigger in addiction recovery programs. And I can tell you that if you deprive animals of food in animal studies, you increase the rewarding effects of every drug of addiction that I'm familiar with. Low glucose levels predicted higher aggressive impulses in a 21-day diary study of married spouses, Bushman et al. Yeah, well, think about that with your significant other. I'm not going to speak to myself, but I'm guilty as charged. Anyway, consistent with a shift toward negative reinforcement motive, individuals with more food addiction-like symptoms reported less anticipation of positive reinforcement from eating. And then tolerance and withdrawal are produced in response to ultra-processed foods, which is some relatively new papers by Ashley Gearhart and her team and others. And I'm sure she'll talk a little bit about that. You can do this in animal models. And so cycles of overeating, high reward versus absence from palatable foods, low reward akin to cycles of drug use and withdrawal may promote transition from casual to compulsive eating. Opponent process-like responses to highly palatable food combined with absence or low reward dieting are hypothesized to yield hyperkatifeia with hyperhedonia and increased stress reactivity. Hyperkatifeia promotes relapse intake of palatable food via negative reinforcement mechanisms. So as I said earlier, as individuals progress toward compulsive food intake, the prime motive for eating palatable food is hypothesized to shift from reward to relief with self-medication of the hyperkatifeia that emerges when preferred foods are not eaten. So just to show a little data and a focus that we've been working on for many years, we've done a lot of work over the years on a peptide known as corticotropin-releasing factor. It was discovered in 1981 by Wiley Vail at the Salk Institute. I was actually there. I was the first person to inject CRF into the brain of a rodent and look at its behavior around 1981. Subsequently, most of you know by the diagram that's on the left-hand side there that CRF drives the hypothalamic pituitary adrenal axis, but it also drives the sympathetic nervous system and it also drives and marks the extended amygdala that I talked about earlier. So this diagram, you can superimpose opioids, you could superimpose alcohol, and you can superimpose overeating or addiction-like eating. And so we do see withdrawal-induced increases in CRF during withdrawal from palatable foods. CRF antagonists will block the anxiety-like responses you see in animal models from palatable food. Palatable food intake increases in self-administration can be blocked by CRF antagonists. And stress-induced reinstatement of palatable food eating can be also blocked by CRF antagonists. And this has been done now with CRF1 antagonists, which are small molecules, but also with the peptide CRF antagonists that were injected into the brain. Some of the work that we did, we showed that acute abstinence from palatable food increases CRF immunoreactivity and mRNA expression in the amygdala. Here's an example of that. And it's the only real data slide I'm going to show you, but I thought it was pretty dramatic. So this palatable diet was a 50% sucrose diet. It had the same number of calories as the regular boring rat chow that rats eat. But when they're given the palatable diet, they snarf it up very avidly. And when you remove it, they go through withdrawal, which I'll talk about in a second. But they also show this dramatic increase in CRF activity, both mRNA, but also in immunoreactivity reflecting release of the peptide in the central nucleus of the amygdala, key part of the extended amygdala. And then as I alluded to, CRF1 antagonists block the anxiety-like effects in rats withdrawn from palatable food. CRF1 antagonists blocks decreased motivation for seeking less palatable food in rats withdrawn from palatable food. CRF1 antagonists injected into the central nucleus of the amygdala block excessive food intake and anxiety-like behavior in rats withdrawn from palatable food. And then a CRF1 antagonist injected into the basolateral nucleus of the amygdala blocks the hypophagia of chow diet in rats withdrawn from palatable food. So it appears that the CRF1 antagonists are working not only in the central nucleus, but in the input to the central nucleus of the basolateral nucleus of the amygdala, further adding to the intriguing effects of how CRF antagonists could be impacting this hyperkatifeia. So I wanted to end on one study that, you know, until I prepared this talk, I had forgotten about, but it was done in the IRP in 2016 by Dr. Epstein and his group. But a prelude to that, several studies have shown greater extended amygdala reactivity in response to pictures of high-calorie versus low-calorie food. Again, Ashley Gearhart's group, and she'll talk about that, I'm assuming, and others. Obese women, as compared with healthy-weight women, showed greater extended amygdala responses to pictures of palatable high-calorie food, but less preferred low-calorie food, but not less preferred low-calorie food, which were steamed vegetables versus cheesecake. I hope you all like cheesecake. But the paper that I was really intrigued to exhume from the literature was a CRF antagonist, generic name is pexacerfon, it's not on the market, showed positive effects in blocking stress-induced eating and food craving in a human laboratory trial done at NIDA. These are some of the data that Dr. Epstein presented in that paper, and they used a randomized double-blind placebo-controlled human laboratory study. They had stress-induced food consumption and craving that were assessed in a bogus taste test and using visual analog scales. These individuals, the bogus taste test was that they were told that they were doing a taste test, but they were actually surreptitiously measuring their food intake, and that has a story to it that I'll explain in a second. But anyway, the craving after the stressor, which was a difficult math test, actually went down in the pexacerfon group, and that's the left-hand panel there, you can see that. And it's statistically significant, even with the small n, and you can see a general trend toward a decrease in night craving in the individuals who were treated with pexacerfon. They had to stop this trial early. You can see it's a low n, 17 in the placebo group and 13 pexacerfon group, not because there were any untoward effects of pexacerfon, but because there's a law out there somewhere that says you can't use a bogus test when you're giving medications to patients, and so they had to stop the trial. And they write at the end that if they wanted to redo this study, they'd have to get the law changed. So keep that in mind if you're into the bogus taste test kind of design. So that's all I was going to tell you about today. I wanted to basically emphasize the point that there's a hedonic shift that occurs in all addiction, but it also may occur with highly palatable foods and addiction-like eating that we see in human beings and in animal models. The argument is that as you progress through the cycle, you generate an allostatic load on these systems I've been talking about, largely in the extended amygdala. We call this allostasis, where basically it's stability through change, so you're fighting to return to the normal hedonic state, and you're successful up to a certain point, but ultimately you descend into the pathology of what we call addiction. And there can be all kinds of loads on this system, and I'm sure that Ashley may talk about some of this as well, but genetic, epigenetic loads, depending on your genetic makeup, childhood trauma, psychiatric comorbidity. We've heard a lot about this at this meeting in the context of addiction and alcohol use disorder, but excessive, this says excessive drinking, but it could be excessive palatable food intake. And I think that's a really important point, that taking the substance itself ultimately creates an allostatic load in these hedonic systems that we talk about. So what I've told you is drug addiction and addiction-like overeating represent a dysregulation of incentive salience, pathological habit, reward stress, and executive function systems. I focused on the reward stress systems corresponding to dysregulation of neurocircuitry with focal points in the basal ganglia, extended amygdala, and prefrontal cortex. I focused on the extended amygdala. Gene Jack talked about the basal ganglia and prefrontal cortex in some detail. Individuals with addiction and addiction-like overeating are miserable. You may not agree, but I think, you know, certainly in an addiction, this is the case. Certainly with opioid use disorder, this is the case. Certainly with alcohol use disorder, this is the case. And certainly with individual case histories with individuals who overeat palatable food, this is the case. And so they suffer a hypersensitive negative emotional state, which I shorten to hyperkatifeia. Animal models show that hyperkatifeia-like responses associated with shifts from palatable to non-palatable food may involve activation of brain stress systems, such as CRF and the extended amygdala. Preliminary translational work in humans also supported the link of extended amygdala and CRF in addiction-like overeating. And neurobiological substrates meeting negative reinforcement in addiction-like overeating may provide insights into additional sources of motivation for compulsive food seeking. So thank you very much. I want to acknowledge Eric Zaria and my colleagues, Eric Cottoni and Valentina Sabino, who were K99s during this period we were working in this area, and Mike Ahrens helped me with some of the slides. So thank you very much. Thank you so much, Dr. Koob. What an excellent talks we've had so far. I've got some hard acts to follow. I'm going to be finishing up with our last talk, and then we'll be going to Dr. Volkow as a discussant, and then we'll be doing Q&A. So I'm going to speak to you now about evidence of a highly processed food substance use disorder. You know, right now, we don't really capture this phenotype we've been talking about today of this addiction-like overeating in the DSM at the moment. And so when I was in grad school, I actually came in to be an alcohol researcher, but I pretty quickly got interested in this new food environment and all the harm it seemed to be doing. And so I got intrigued with how could we maybe operationalize and identify people who were being most likely to show this addictive profile in their intake. And so we did something that was, I think, pretty common sense, which is to take the existing diagnostic criteria at the time it was substance dependence, now it's a substance use disorder, and we just applied those diagnostic criteria to the intake of highly palatable, highly processed foods. And so the current version of this scale I created, the Yale Food Addiction Scale 2.0, applies the DSM-5 substance use disorder criteria to the intake of highly processed foods in the last 12 months. It assesses things like loss of control over intake, cravings, inability to cut down despite a desire to do so, continued use despite negative consequences, tolerance, and withdrawal, which we know is so important from the last talk. It has a total of 35 items, and it provides two scoring options, a symptom count that goes from 0 to 11 symptoms, and a profile that reflects what we do with the DSM of a diagnosis of food addiction, which is two or more symptoms plus clinically significant impairment or distress, and there's a mild, moderate, or severe scoring option. At this point, the Yale Food Addiction Scale has been cited over 1,000 times and has been validated and translated into over two dozen different languages, so it's a pretty well-established measure in the field at this point. Based on over 200 unique empirical articles around the globe, we're starting to get a sense of what the prevalence of this food addiction phenotype might be. So when we look at clinical samples of individuals presenting for things like obesity treatment, about one in three adults would meet that diagnostic threshold on the YFAS. If we look at just a general community sample, we see that it's about 14% of adults. This is really similar to the threshold that we see with things like alcohol, another legal, easily accessible addictive substance, where the current prevalence rates are somewhere between maybe 14% to 18%, depending on the study that you're looking at. What I would say is really unique in the context of considering a substance like highly processed food as potentially addictive is what we see in children. So if we look at samples of children with overweight, it's 19% of children are meeting this food addiction threshold. If we look at just a general sample of children in the community, we're at 12%. Of course, we don't see alcohol or opioid or cocaine addiction in children at this sort of level because generally we protect children and reduce their exposure to highly addictive substances. But we currently see that in America, over 60% of caloric intake in the United States in children is now highly rewarding ultra processed foods. We see that the likelihood of receiving an addiction of highly processed food addiction increases with body weight. So you can see on the x-axis, you can see mild, moderate, severe, probably the easiest one to look at is the total food addiction profile. And you can see that as it goes up from normal weight to overweight to obese status, that the prevalence of the food addiction phenotype goes up in a stepwise manner. I always note that it isn't completely overlapping. We see that obesity can be a very multifactorial condition, and we see that about one in three individuals with obesity are meeting this food addiction phenotype. And it is still pretty prevalent when we look at individuals with normal weight. We're seeing around 7% of individuals. To me, this always strikes me of the importance of not necessarily being able to look at someone's body shape and think you know what their relationship with food is, and why I think it's important to kind of use those same behavioral diagnostic criteria we use with other addictive substances to try and really conceptualize this profile. And when I started doing this work, we kind of weren't really fully conceptualizing yet the impact of our current food environment. And so we called it food addiction, because we weren't really sure what else to call it at that moment. And I think that's actually a pretty big misnomer, which is why you catch me continuing to say highly processed food addiction throughout this talk. Because as I mentioned in the intro, we know a lot about how you create addictive substances. You increase the dose of an addictive reinforcing agent, and you make it so it absorbs really rapidly into the system. That rapid rate of absorption is really key. And that can lead to a high addictive potential. And when we look at highly processed foods, we've increased the dose of rewarding ingredients like sugar, like fat, beyond levels that occur in nature, and in combinations that don't occur in nature. But we've also altered the food matrix by stripping out fiber and water and protein. And so you can eat those foods much more rapidly, they melt in your mouth more rapidly, they're digested more rapidly. And so the delivery of those reinforcing agents is also heightened. And so my doctoral student who's now at Drexel University on the faculty and I did some work where we had people fill out the Yale food addiction scale, and then we asked them to rate different foods that were nutritionally diverse about what foods they were most likely to consume in that way that's reflected in the YFAS. And I feel like this is one of the least shocking slides I show in my entire career, that the foods that people rated as the highest ones were things like chocolate, ice cream, French rice, pizza, cookies, chips. We've now replicated this in a number of samples of all sorts of different attributes and these guys continue to be the top risk ones. And you'll notice that all of these foods are highly processed. They don't exist in nature, we create them. And all of the top ones are high in both rapidly absorbed refined carbohydrates and fat. And just to kind of note that, in naturally occurring foods, foods either come high in sugar, like in a carbohydrate, like in fruit, or high in fat, like nuts or meats, but not high in both. And so the fact that so many of the highly processed foods we eat are high in both carbohydrate and fat is evolutionarily novel. What foods were at the bottom of the list, again, not a shocking slide. Is foods like apple, corn, you know, beans is at the very bottom of the list. I assume there's an aversive response there if you overeat that. But you'll notice some of these foods are naturally high in sugar, something like a banana, but in the way that they're consumed in the delivery vehicle, you don't have fat, you have fiber, you have water, you have acids that kind of reduce the degree to which it's altering the brain, altering the gut. And so these naturally occurring foods that we want people to eat more of that are nourishing are not the sorts of foods that people report consuming addictively. But I get a lot of questions of, you know, okay, like, can you really say that these sorts of unnaturally rewarding foods, I mean, do they really mimic what we see with other addictive substances and the degree to which they trigger reward? And if we look at something like amphetamine, you know, it can trigger dopamine release over a thousand percent over normal and striatum and midbrain. But when we look at substances that we know are addictive, like nicotine and ethanol, you know, we see that based on micro-dialysis studies that about the amount that they increase dopamine over baseline is about 150 to 200% in mesolimbic dopamine systems. And when we look at ingredients that are in highly processed foods like sugar or actual highly processed foods, these guys are Fonzies, essentially like Italian Cheeto sort of foods, we see that the degree to which they are also increasing dopamine and the mesolimbic dopamine system is between 150 to 200% over baseline. So yes, these foods are not just triggering similar behavioral profiles of loss of control and craving and continued use despite negative consequences, but the magnitude of activation in key neural circuitry of addiction is very comparable. We've also looked in my lab, this is my doctoral student, Lindsey Hoover, at whether this food addiction behavioral phenotype is co-occurring with other addictive disorders. This was really key in our understanding of gambling, which in the DSM we took out of the impulse control disorder section and put it in the addiction section. And some of the evidence there was that gambling really co-occurred a lot with high-risk substance use disorder. And what we see here is that high-risk, highly processed food intake is associated with high-risk alcohol use, high-risk smoking, and high-risk vaping. So these seem to potentially co-occur together in a cluster of behaviors. And we also see that a family history of high-risk alcohol use, a common known risk factor for potential risk for addictive disorders, is also associated with a heightened risk of food addiction, about 135% higher highly processed food addiction for people who had a family history of high-risk alcohol use. And this effect was actually even a little stronger than looking at the association of family history of alcohol use with actual high-risk alcohol use in the sample. So it kind of really speaks to the magnitude of that association. We've looked in my lab at the neural circuitry that's been so key and the talks we've had previously. So we've looked at individuals who vary in their symptoms of highly processed food addiction. And then we've had them look at either a neutral cue of a water glass or a milkshake, a chocolate milkshake, and they've actually gotten little doses of a tasteless solution or a chocolate milkshake in the scanner. And this is a sample of women, none of whom have an existent eating disorder. And even controlling for body mass index, higher yield food addiction symptoms were associated with greater activation to this milkshake cue, to the anterior cingulate cortex, medial orbital frontal cortex, amygdala, and caudate. And these are regions, as we just discussed, associated with craving, enhanced motivation, inhibitory systems, suggesting similar kind of neural parallels with this food addiction profile, even controlling for body mass index. The inhibitory control systems, which we discussed and that were discussed in the prior talks as being a really key part of the cycle, are also associated with food addiction. So this is a big sample from James McKillop's lab, where they found that even after controlling for age and income, symptoms of food addiction were associated with greater urgency, a tendency to act impulsively and rashly when you're feeling emotionally stimulated, and having heightened delay discounting, a tendency to prefer those immediate rewards over long-term rewards that was presented in the prior study, which was a nice setup. But is this clinically meaningful? You know, is there anything we should be paying attention to about this addictive profile when it comes to understanding who might be coming into clinic or who might need help? And so this is the diet fits trial that had 609 adults come in. They were randomized to either a 12-month low-fat or low-carb diet for weight loss. And in this study, they looked at baseline psychosocial and demographic factors to predict in stepwise logistic regressions who was likely to drop out of the study, which about 28% were, and of people who completed, who was more likely to gain weight rather than lose it, which was about 18% of individuals. And what was seen in this stepwise logistic regression is that food addiction was the best predictor of people who were likely to drop out of treatment at 12 months, were 43% more likely to drop out of treatment. And predicting of those who stayed in, those who gained weight rather than lost it, food addiction, again, was the best predictor, being at about 46% increased risk of gaining weight during treatment. So this suggests that these are individuals who are coming in, and we're doing our traditional, you know, eat this, not that, eat healthier, and that they're not responding in the way that we would like them to, and they're at heightened risk. And I would argue that's likely because we're not targeting many of these addictive-like mechanisms that are so essential to driving the behavior in our sort of treatments. And just broadly, we see that even comparing to BMI and controlling for BMI, that James McKillop's lab, again, found that food addiction's associated with a lower quality of life across every single domain. And this is overall quality of life is what I have circled there for you, but if you look at the specific subsets of physical and psychological and social and environmental, food addiction symptoms predicted lower quality of life to a much stronger magnitude than body mass index did, again, suggesting that these are people who are suffering that we're, you know, we're not assessing, we're not diagnosing, we're not kind of capturing in our current clinical profiles right now. And I think it's really exciting to think about if we do start to understand and identify and conceptualize this addictive eating phenotype based on the current substance use disorder criteria, there's a lot of exciting and innovative substance use disorder treatment approaches that could be used in parallel. So there's actually a small naltrexone bupropion study finding that that was effective in reducing food addiction symptoms in adults. It was a small study and needs to be replicated. But there's also lots of 12-step based addiction programs that are out there. Overeaters Anonymous, Food Addictions Anonymous, 12-step programs have been out there since the 1960s, and there's thousands of meetings around the world. I think right now there's this huge call for those sorts of treatments to be evaluated. You know, we haven't been able to, there hasn't been scientific evaluation and kind of rigorous randomized control trials in the way that we would like. I would think in part because we haven't really been scientifically seriously conceptualizing this addictive profile. And so there's clearly demand given this huge clinical demand for addiction folks' treatments for eating, but we need to kind of continue to evaluate and investigate and consider different treatment approaches like as well as cognitive behavioral therapy, motivational interviewing, trauma-focused treatment. We see really strong associations with food addiction and childhood adversity and PTSD in my lab. Harm reduction type models, contingency management. We really could be creative here and thinking about how we use substance use disorder-based treatments to improve the outcomes of individuals and potentially match based on people's different risk factors. We really need the science to do that and to guide us. So I'm going to kind of end with a thought experiment, which is, you know, what is the evidence that these highly processed foods are not addictive? Like I think I've tried to show like a lot of evidence of different things to show the parallels with addiction. Some of the other researchers, you know, they're contributing to hundreds of thousands of preventable deaths every year, surpassing alcohol on par with tobacco. They trigger dopamine release at a similar magnitude as nicotine and ethanol. They're consumed compulsively, craved intensely, highly reinforcing. There's now over 400 empirical articles conceptualizing a substance use disorder with highly processed food. Is it possible that given this scientific base, there's at least a need for this to be a provisional diagnosis in the DSM-5 to help guide future research and science and help us really evaluate the utility of this construct? And so I just want to do a quick thank you to my lab, the Food Addiction Science and Treatment Lab at the University of Michigan. Initial funding I received from Rudd Center for Food Policy and Obesity. And my funding I received from NIDDK and NIDA. And if you're interested in any of the scales I talked about today, you can go to my lab website and they're available free for download as well as scoring. And we do have a withdrawal scale as well around highly processed food that is available for free at our website. So you can find that here. I will now welcome our discussant, Dr. Volkow, up to speak. Thank you very much. Good morning, everyone. It's a pleasure to be here. I haven't been in the American Psychiatric Association in person for more than three years. So it has been wonderful. And I think there's no better way to be here and listen to such a remarkable panel and such great presentations. It was in 2007 that Dr. Chuck O'Brien and I had an article on the American Journal of Psychiatry asking the question, shouldn't the DSM-5 consider overeating and obesity as an addictive disorder? And even though we provided that basically the information related to the similarity in the phenomenological presentation and data and the evidence that already existed, some of them presented by Dr. Jinja Kwang related to the common neurocircuitry at that time that the DSM-5 committee said, no, the evidence is not strong enough. And that was the end of it. So now we basically see that the science has advanced in ways that if we had had it then, I would have hoped that by then that the DSM-5 would have not been able to say no. Because to me, as Ashley just eloquently stated, let me put the negative thought, the experiment in our brains that foods that are highly processed and rewarding are non-addictive. And I would put, again, the notion as we presented today, you had the elegant presentation of Dr. Jinja Kwang, who has been alongside our team initially at Brookhaven and then at the NIH, and also with his close collaborations with a laboratory in China, being able to delineate the neurocircuitry that relates to the enhanced motivation to seek food and the effects of treatment on that neurocircuitry. And then very eloquently, too, Dr. George Koo has shown to us, which he had shown before doing it for food addiction, that this is a component that is fundamental for actually driving drug taking in people that have a substance use disorder. And that it is not the individuals, just like in the case of obesity, that are seeking per se, voluntarily that state, but it is the escaping of a state that he calls hypercatifeia. But it's very hard for my brain to actually process that work, because it is negatively conditioned in my brain to be something with an F and a K, which is very negative. And I'll come back to it, because I think that this actually is telling us something crucial about the process of addictive behaviors, both in the positive reinforcement and in the negative reinforcement. And then Ashley, with basically providing us the tools by building up a scale that has validity and reproducibility and predictability, I recognize that based on the symptoms of what we call a substance use disorder, actually is predicting eating behaviors. So this gives us on the one side the neurocircuitry and the phenomenological presentation of that neurocircuitry, but on the other one, the tools that have actually shown that this construct validated both preclinical, clinical, and by its predictive characteristics is a valuable one. As I think about it, and I am coming back also to Ashley at the beginning, that saying should there be a diagnosis for food addiction? And I had also put that forward in 2007, and my answer is yes, and why does it matter? And that's what I want to focus on. It matters because it gives us an understanding about the process that people actually, that leads people to overeat in ways that are clearly very detrimental to their health. And that is relevant both for prevention, that is relevant also for treatment, but it's also crucial for public health in many, many ways. Ashley also started by telling us the story of tobacco. There were no people addicted to nicotine at the beginning of the 20th century, and what led to nicotine addiction was, of course, the ability to deliver the nicotine substance in ways that were extremely rewarding. And that has probably been one of the most devastating consequences to public health, the negative effects of smoking, that we have been struggling since then. Similarly, the patterns that we observe in food are actually following the same strategy, not surprising. And it's a strategy that is actually likely to be 100% effective. And if you think about it, you say, why would it be 100% effective? Well drugs actually epitomize, the classical drugs epitomize for us the total disruption that they can generate in our motivations to pursue behaviors with its devastating consequences, despite any rational thinking to try to understand why someone will choose to take that drug despite all of its negative consequences, which we obviously have dismissed by saying the person is seeking a rewarding pleasure and that moralistic perception that has created an enormous amount of stigma. That also very strongly permeates obesity. And I basically, in terms of how people react to it, people that are obese cannot hide the obesity and are terribly stigmatized by our society. That further contributes to what George has been describing so importantly as one of the most powerful triggers of the behavior of addiction, when you are stigmatized, when you are stressed, to actually lead them to overeat. So why do I say this in many ways is relatively easy to understand why drugs actually can produce this phenotype? Well, they are tapping into the main neurocircuitry that drives our behaviors, that leads us to make choices. It's fundamental and crucial because without it, we wouldn't survive as individuals or as species. If I am hungry and that does not take preeminence in my brain to go and get the food, I will not survive. And that hunger is basically the energizing of that hunger to move my movements towards reaching the food is a dopaminergic circuit that actually allows me to do two things. One of them is, of course, a sense of reward when you first encounter that stimuli. And the other one, which actually is common to both, whether it is drugs or whether it is food or whether it's another behavior that produces compulsiveness, just as maybe video gaming, as maybe hypersexuality, all of those are associated with a state of well-being when you are intoxicated. And as George mentioned, once the intoxication goes down, there is a state of enhanced dysphoria or what he describes, but I have trouble always saying that word, hypercatifeia. My amygdala gets activated when I say it and my avenula also. Yes, it is intended, basically, it's an onomatopoeic work that actually generates the states for a microsecond. But it's also the one that actually, very elegantly, too, Dr. Jin-Jack Wang showed with the avenula, which is another system there, too, extremely important in generating that negative reinforcement component. So yes, the dopaminergic system drives your motivation to active your hunger, get the food, and then you are satiated. But it also enables you to generate the conditioned response. And that conditioned response is both for the positive sensation that you get when you encounter the food that leads to this unexpected somatosensory pleasure and relief of the hunger. So it's not just that you are feeling the pleasure, you are relieving the hunger. That also leads to the negative reinforcement. So the conditioning to the positive reinforcement is that dopaminergic signaling stimulating neuroplastic changes brought about by glutamatergic enhancement in certain neurocircuits that will lead you in the future to expect that reward when you are in the same situation. When that reward disappears from your body, you feel, as he was saying, this sort of like dysphoria, depending how advanced you are in that trajectory, it may be mild. And if you are advanced much more into that trajectory of repeating that reinforcer, much stronger. And that is driving, just like actually hunger is a negative state, drives your behavior to get out of it. And so this brings me, and you get negative sort of condition to that negative reinforcement. You learn that when you're feeling like that, taking that reinforcer, whether it is food or drugs, will get you out of that state. So this brings me to the other issue why it matters very much in terms of prevention. And this is something that we think and think and think in the substance abuse field. We know that not everybody that get exposed to drugs becomes addicted. And the same thing, we know that not anybody that get exposed to this obesogenic food becomes addicted. We know that there are extremely important genetic factors that underline, and now we know that there is overlap in some of the genetic factors that make you higher at risk for certain substance use disorders and higher at risk for overeating and obesity. But we also know that adverse childhood experiences are a key component that makes your vulnerability. And I would put forward, because this is one of the things that we're basically tackling right now to get a better understanding, what we have always described as a social determinants of health is another extremely crucial component of the vulnerability for addiction and obesity. A couple of years ago, it must have been five years ago, I was visiting West Virginia. And I was struck when I was visiting because that is at the epicenter of the overdose crisis. That is where we have the highest number of people dying from overdoses from opioids. And this reflects, again, a state of despair where the individuals do not have jobs and don't try to escape through them to the use of drugs. And I was there and I was noticing the high, high prevalence of morbid obesity. And certainly this is to be expected, because it is the environmental adverse effects that drive these diseases that I would put forward are diseases of despair. And why do I actually discuss this? Because on the one hand, if we want to address prevention of substance use disorder, prevention of obesity, we need to address the social determinants of health that are leaving people without alternatives. Try to find healthy food in some of these towns. Try to find anything that looks healthy in an airport in some of these cities. That's actually, that are at the basically beltway of many of the obesity problems. Individuals don't have choices. Food deserts are real. And so if you are growing up in a deprived environment where you, what you actually get conditioned to relieve your hunger is food that is highly obesogenic, you will be strongly conditioned to it and you don't have alternatives. And as you live and grow up in this environment with restricted alternatives, our brain is designed to seek out diversity, to seek out reinforcers. It feels good. It's hardwired because it has a purpose. Feeling good leads us to do things that can be positive. But if you are constrained and you don't have alternatives, then that escape is the use of obesogenic food or the use of drugs. So it's therefore not surprising that when we look at actually who is at higher risk, within our country, look at the map of obesity, look at the map of poverty. They basically overlap. And so that's what I say in terms of prevention. In terms of treatment, I think it behooves us it is very relevant because there are multiple opportunities to actually gain traction by understanding what are the signals that are actually valuable in treating obesity because they may be valuable in treating substance use disorder. Let me show you an example. Leukagon-like peptides, probably one of the most exciting and potentially important medications for the treatment of obesity, currently approved mostly for the treatment of diabetes. It is showing to significantly reduce weight. And trials are starting to show, not surprisingly, curiously, it is also showing that it is reducing alcohol drinking, including binge drinking. Prevention technologies actually now enable us to basically target specific brain regions and networks that are disrupted in multiple psychiatric diseases. This gives us an opportunity by understanding better, ultimately, what are the neurocircuits in a general sense, but also in a personalized level so that we can target it to that individual. And finally, I do want to end my presentation because I saw someone showing me something like that said that one, I assume it's that one minute that I have, 30 seconds. So the one on public health, because it's ultimately if we can make changes in our environments, in the way that we incentivize industry, in the way that we support families that don't have access to the resources to buy healthy food, we can have the largest impact. If I were, and I'm going to do actually another thought experiment, I was thinking about it, I would ask ChatGPT, I would ask ChatGPT, what is the most powerful reinforcer? I'm curious to see what it would say, because of course, ChatGPT will do a common denominator of the data sets that are out there and the information that we get plagued by. And I'm thinking, I'm trying to predict what the response may be, whether it is basically money as the most powerful reinforcer, or whether it is food. And food basically drives, it's a key driver. And the neurocircuitry in the brain actually has evolved to maximize and to ensure that they are redundant systems that drive our behavior to ensure that we get sufficient food to it. So if anyone has ChatGPT, please ask him that question, and then we can ask them for that response. And with that, I want to thank you for your attention. We're going to do two things real quick, we're going to get the speakers up here for a panel discussion. I'm also going to set up a Q&A. up another survey about whether you think it's time for some consideration of a highly processed food use disorder in the DSM. I'll pull that up. So we'll now be taking questions and I'm happy to kind of navigate that. Yes, please. This is a question for Dr. Volkow or anyone on the panel. What are your thoughts on the legalization of cannabis, the increased availability of cannabis and highly addictive foods? No, thanks for that question. I have many thoughts about the legalization of cannabis, but because we are in a panel regarding food addiction, I'm just going to tell you as they were the presentation, what thoughts came into my brain. I was sort of actually in terms of what is the impact of the excess and availability of cannabis as a substance, how it is influencing our food patterns, because we look at the reinforcer. So the issue is can we substitute one reinforcer for the other? We do know, for example, in the case of individuals that have undergone gastrectomy for obesity surgery, there is an increased risk for alcohol drinking. So we substitute one from the other. And that is, I think, an aspect that I would be concerned about, I mean, that it has, there is an association. And the other one that I would speak about, an association that was not yet discussed, but I've always been fascinated by the fact that alcohol has energy. So it is the only substance in general before you have the edibles of cannabis where you can actually consume it with calories. And based on studies out there and our own studies, the evidence that these energetic effects of alcohol are actually playing an important role in its reinforcing and rewarding effects, one that we have not paid sufficient attention. Sorry. I asked for the role of ghrelin, molecular, and cholecystokinin in this circuitry is the first question. And the other question is to circuitry in the path you show. I looked at you act in the cingulate anterior. This is motivation. It's not reward. And not in the 25 area. It's the area of the reward. In the end of the chyosin corpus in the pole anterior. This is only the question. Sorry. Would anyone like to take the ghrelin question? And I can respond to that. Ghrelin is a very interesting topic that is being known that the ghrelin, they have connect to the ventral tegmental area that enhance the dopamine. And that is that the only peripheral hormone that enhance our eating. The rest of the peripheral hormone actually suppress our eating, including insulin and GLP-1, those kind of things. However, we cannot use that ghrelin for anti-ghrelin for the treatment of obesity. It fail. It never really happen. So turn out that GLP-1 is a better choice so far. Regarding a quick response to the ACC question. It's true. Like thinking of ACC as I believe it was Jean-Jacques shown that ACC kind of thinking of it more in like an inhibitory control way. But what we're seeing often with both substance use disorders in the context of obesity and addictive eating is that oftentimes you both see like kind of caudate, striatal activation in response to the cues and also that inhibitory circuitry. And in people who are successful regulators, the activation and the control circuitry seems to down-regulate and reduce the striatal activation. But for people who are not successful, there usually is an attempt and you see kind of some executive control activation, but without the commensurate reduction and striatal cue-based activation. So I think that's what's going on there, but we didn't do connectivity in that model. That was kind of before that was coming out regularly. So it'd be an interesting thing to look at the connectivity. Rob? Wonderful symposium. Thank you all. I'd like to address the public health issue that Dr. Volkow just sort of briefly touched on. One of the biggest obstacles of this field actually comes from Europe across the pond because there's a group out there that believes in this thing called eating addiction as opposed to food addiction. That's not semantic. It makes a big difference because if it's eating addiction, it's the patient's fault. And if it's food addiction, then the food industry bears some culpability. So this is not a little problem. This is a big problem. And I think one of the issues is how do you reconcile these two phenomena? Ashley debated Johannes Heberbrand and the AJCN just last year on this issue. My question is based on the neuroimaging, based on the empiric data, based on the biochemistry, can we actually answer that question in some meaningful way, number one? Number two, can we identify which specific foods are the addictive substance? Number three, we were talking about ghrelin being an important one just now. Well, there is one particular substance that does not suppress ghrelin when you consume it. It's called fructose, which is sort of my pet hobby horse. But it is the most addictive of substances because it is the thing that actually activates that nucleus accumbens. Can we come to some sort of, shall we say, rational thinking about how to apply this regards both addiction but also toxicity? Because you can't do anything public health wise on addiction. Otherwise, there wouldn't be Starbucks. We have to add the toxicity to the mix, and no one has talked about that at all yet. Yes, and I think, thanks for that question, and I think it is one that we should all think about. I mean, first of all, I love a Starbucks, and I would be in withdrawal if there was no Starbucks, and I'm not obese. But I have multiple choices. And that's where coming back to your first question, should it be food addiction or eating addiction? I would say food addiction. You have drug addiction. If there were no drugs, I could have the drive of hypercompulsive behaviors. And I can tell you, I'm someone that has that hyper drive. Because of my multiple choices and alternatives, I haven't focused in only one that could have pathological consequences. Which brings to the notion, I mean, obviously, this vulnerability for addictive behaviors is something that has evolved and may have had benefits. Otherwise, it would have disappeared from our genes. So it's like the notion of people that have a vulnerability for obesity when you put them on obesogenic environments. But otherwise, that genotype vulnerability has enormous advantages. They can survive when food is not available. So that's why I would basically, in a very straightforward set, it's a food addiction. Well, indeed. We've got 40% of Americans who are teetotalers, never touch alcohol. We have 40% of Americans who are social drinkers. But we have 10% who are binge drinkers and 10% who are chronic alcoholics. Yet, despite that, we say that alcohol is addictive. So just because it's not addictive in 100%, we still say it's addictive. Can't we say the same thing about this? Well, I think that, and it's an important question, and I think that where one can delineate ways of describing it, I think, I mean, in drugs, I say drugs that have the potential to trigger addiction. And they are foods that have the potential to trigger addiction. You are not going to become addicted to a lettuce without dressing. Just know. So the potential of addictiveness, and that's why basically we came up with that notion of that dimensionality of addictiveness, because not foods are equal. And even when I get exposed to highly addictive food, I basically can self-regulate. But again, I am in a privileged situation and not everybody's there. But it is, I think, a very relevant aspect to address the categorizations of food vis-a-vis their dimensionality, the addictiveness potential, as one of the parameters that one should be looking at. But I'd love to hear from my colleagues. Yes, I, when Ashley invited me to join this symposium, I, she came out with the name of food addiction. I said, well, if you say food addiction, then I won't join it, because it's going to have a lot of controversial issue from the audience. And so she sent her slides, and then I agree, because not all food are equal. And then she had a list of the food, and those are, it never happened maybe 100 or 200 years ago. All the food right now we are eating, a lot of them are already modified. Even apple, people have the artisan apple, it's very, very delicious. And if you go to, maybe 50 years ago, you go to that orchard, you cannot eat many of the apple, because it doesn't taste that good. And so all those are the things is happening in the last maybe 100 years or even 50 years. So I think we need to treat the food different from our ancestor. Those food are very, very, we call that, we don't eat food not in the original form, that it has a meaning involved. And just for the sake of timing, because we are a little over our time, I don't know, in the back, do you know if someone is using this room after us? You don't know. Okay. Don't want to, you know, hijack their room. But I think we probably have time for one more question from the audience, and then we should probably, I'm happy to stick around, and I don't know if any other panelists started to take questions offline as well. So one more question. Thank you. Thank you for this wonderful panel and presentation. I'm Cynthia Myers Morrison. And in the intergenerational aspect of this whole issue, we need to, I think, look earlier in the progression, so that we need to look at the intergenerational impact from the person who is perhaps five generations away earlier, and what that epigenetic impact has been. David Barker has been talking about this and, you know, phenotype of, previously, of adult disease in infants. How might we look at this and get to the younger people before they have a pregnancy, which is the time period at which the hormones in males and females are at the wrong place at the wrong time, if they're obese and overweight? How can we get to those people prior to pregnancy, preconception, to alter the intergenerational aspect of this? I'm happy to. We actually just published a paper with a colleague, Dr. Julie Lumang, who's a pediatrician at University of Michigan, who's wonderful. And we looked at maternal profiles of eating, food addiction, high BMI, dietary restraint. And the only predictor of infant overweight, where the infant was only four months old, was food addiction, the maternal food addiction. I think, again, kind of going back to Nora's point, this is really going to be a systematic change. It needs to be environment, and there needs to be, particularly considering privilege and resources. We find, in analyses we just completed yesterday, a 238% increase in the highly processed food addiction profile for individuals with food insecurity. And so access and reduction of, I would say, kind of aggressive marketing and promotion techniques for foods that aren't nourishing health, but are nourishing profits, is probably where we need to go in that kind of systematic way. You know, there's been a series of studies in animals and in humans that actually have shown that the diets that you give to the pregnant mother, where it's a rodent or a human, basically conditions the infant to preferences for those foods. So if you give them very high content sugars, then those infants will have a preference from them. So you're already conditioning them and imprinting them in terms of what their choices are going to be later on. And there's also a lot of work that forum universal prevention interventions that were targeted for substance use disorders, targeting children and the families, showing them healthy behaviors that they actually prevent obesity in girls, which is one of the increases in risk associated with poverty, whereas in boys it's much more the use of drugs. So interventions positively influence both. So I completely agree, this has to be from early on in pregnancy. Or even preconception, please. Thank you. Thank you all for joining us, and thank you for the esteemed panel here who joined us today. Thank you so very much. We appreciate your time.

substance use disorder

highly processed foods

food addiction

obesity rates

diet-related diseases

ultra-processed foods

dopamine dysfunction

sugar and fat

hyperkatifeia

negative reinforcement

social determinants of health

DSM-5

public health interventions