Friday, June 3, 2011

New Podcast Interview, and My Thoughts on "Food Reward"

First off I wanted to link to my latest podcast; this one is with Michael Ostrolenk at the Voices For Hope Podcast.  I had a great time talking to Michael, and we managed to squeeze a lot of me talking in the lean 17 minute interview.  It's funny - since in my line of work I typically do a lot of the listening, sometimes when people ask me questions I can really get going…

Evolutionary Psychiatry at Voices For Hope

Thanks Michael!

And now onto the gentlemanly duel of mild-mannered, gorgeously-referenced, thoughtful posts between Stephan Guyenet and the Jaminets at Perfect Health Diet - if "food reward" is a dominant factor in obesity, should we be eating a new brand of "bland" paleo?  Is obesity regulation in the brain, the liver, the adipose tissue, or the gut?

I will approach the question(s) a bit from the hip and from a clinical perspective, focusing on the far end of the food reward and obesity spectrum (which certainly will not describe all those who are obese) - the binge eaters.  For a little (referenced) perspective on the neurobiology of binge eating, read my posts here and here.

So… what do I like about the "food reward" theory of obesity - (in the briefest of nutshells, the idea that constant exposure to overly palatable food overwhelms our natural feedback mechanisms and causes us to overeat)?  This theory is brain-centric, and I'm a brain-centric sort of person.  It is similar to addiction (and involves many of the same neurotransmitters and brain areas) - an addiction is also tough (or impossible) to shake, involves inflammation as part of the brain pathology, and seems to afflict people along genetic lines.  Some folks can shoot up a bit of heroin, for example, and never feel the urge again, while others get a prescription for percocet after a work-league softball injury and are off to the races, snorting oxycontin and spending $300 bucks a day.  The numbers for addiction and dieting are comparable - quitting smoking cold turkey, for example, has somewhere around a 5-12% success rate long term.  Any and all diets seem to be similar - 95% of people regain the weight within 5 years.

The treatment for addiction is to abstain, one way or another.  A certain percentage of alcoholics can, one day, go back to moderate drinking, but some will never be able to touch alcohol again or end up back in the sober house without driver's license, job, or family - even 15 or 20 years into sobriety.  If "food reward" is a problem of overly palatable food, then the solution seems to be to go bland.  A compelling argument, really, and seems nicely in line with an Eastern philosophy of striving towards the state of wanting nothing.  Kessler in The End of Overeating: Taking Control of the Insatiable American Appetite calls the sugar/fat/salt combo in industrial, processed, and restaurant food "hyperpalatable" - and for him the solution is "food rehab" - abstaining and developing a sense of disgust about that sort of food.

The Jaminets are concerned that our brains have a food reward system for a reason - succulent lovely amazing fruit and bone marrow and drippy yummity steak are highly nutritious and good for us.  Should we be deliberately trying to go bland in the name of dropping pounds?

Here's where my clinical brain and experience with patients gets involved.  I've talked to a lot of people struggling with addiction over the years, and a lot of people struggling with binge eating, bulimia, or some variation in between.  And, I have to say, the struggles and cravings and relapses and descriptions people relate to me about their bingeing have very similar flavors, whether you are bingeing on Little Debbies, Taco Bell, or Jack Daniels.

There's a love affair with the food or drug - thinking about it, craving it, desiring it, then a shift into automaton binge so that the lead-up is typically far more pleasurable than the actual event.  And always along for the ride comes some sort of awfulness, even putting aside the guilt and recrimination.  Often when people shoot up heroin for the first time, they vomit.  Cigarette smoke - it's nasty, you cough, you smell - it's unpleasant.  Cocaine stings the nose and leads to sudden euphoria followed by a much longer period of irritability and depression.  And, for the most part, the food that humans typically binge on is.. well… kinda nasty (seriously, look at that bag of creamsicle oreos in that link to Melissa's blog!).  It's too sweet, has crappy texture, smells of chemicals - it's Taco Bell meat "product" or rancid oily Pringles or gut-bursting amounts of slippery pasta.  For most people (including myself), those healthy, magnesium and copper containing richly flavored low in O6 bars of 85% dark chocolate (intense, addicting chocolate) can be lovingly divided and savored over a week or two - but if I buy the toffee version (34% cacao, milk chocolate) I have to divide it with my kids or I will easily gobble down the whole bar and end up with a sickly feeling and a tummy ache.

So I don't know that straight-up palatability is the end all be all - though Stephan's experiments in treating obesity with low-reward food that he references are fascinating, and he might well prove me wrong.  I think the similarity between the hyperpalatable industrial food and the hard drugs is that they are all (somewhat metaphorically) poisons, but we take the dose anyway, and need bigger and bigger amounts.

So far as obesity - and now I'm talking about the general problem, not just the subsection of serious binge eaters and subclinical versions of that - I think that in some people, the problem is in genetic vulnerabilities in the reward system in the brain.  In others, it's a methylation problem in the liver.  In others, and issue with gut flora.  Or combinations of all of the above, and many other things I'm certainly not an expert in.  All the pieces are related, all could affect the ultimate downstream leptin areas in our noggins.  So perhaps some folks will need to go bland, or at least do so for a while as the inflammation goes down.  Others can dive into the bone marrow salad dressing, eat nectarines dripping with juice, and use the pepper with gusto.

These are my speculations.  Take them as you will.


  1. Emily you and I are like minded.....there are many causes of Obesity but food reward is not one that I can buy based upon the science. The gate to Obesity is via leptin resistance because its the only way the brain can tell anything about energy balance. One thing neither talked about is the most satifying foods are fats. Only carbs have a special neuropeptide that modulates the hypothalamic tracts. That directly modulates the median forebrain bundle......Carbs.....not fat of protein. Obesity is caused by many factors. And we will need to explore each one. Behavior is a result of what the brain is perceiving. A patients clinical symptoms are a proxy for what is occurring at the receptor level. This is why researchers and clinicians view things differently. Scientists look at one issue in incredible detail and they lose sight of the 30000 ft view that the patient lives in. Our job as clinicians is to take what the researchers have uncovered and marry it with the art of medicine. Taking care of a patient. The real disproof of a food reward is this paradox........we have anorexia on one hand who have ridiculous amounts of reverse T3 and leptin resistance that is among the hardest to treat in an emaciated body and then we have a obese type two diabetic at 300 lbs who also has a high reverse T3 and is leptin resistant. They have the same biochemical problem with radically different phenotypes. Food reward is not playing a role in humans in my opinion at all.

  2. In my opinion, even if we define "food reward" very specifically, as something that lights up specific set of reward circuits in the brain, we still haven't said anything interesting. Blaming obesity on "food reward" is like blaming alcoholism on "alcohol reward": it's just restating the problem.

    The more important question is "What causes foods to be rewarding - but not satiating?" If a food is rewarding and satiating, then we'll seek it out, but we won't overeat it. It's the foods that reward but don't satiate that put us into an addictive cycle.

    Here's my attempt to answer that question: Why Snack Food Is Addictive: The Grand Unified Theory of Snack Appeal. I'm very interested to know what you think.


  3. Great post Emily! I'm totally with you that palatability isn't the end-all be-all. For one, whether or not it's a major factor, all of those excess SAD calories definitely have a downstream effect on the liver, gut, and more.

    So while I (poster child for BED) do find that avoiding SAD foods (tho not going bland) is a huge help wrt appetite and compliance, that's probably not sufficient.

  4. I wonder if part of the problem (not the severe obesity perhaps, but the general weight gain so common for most people these days) isn't the sheer diversity of food available. With out of season food and food from all over the world, and diverse cuisines, one need never be bored. Being bored with food isn't such a bad thing: it prevents overeating, and means that one actually appreciates that first June fresh strawberry from one's garden more. But most of us could literally feast three times a day and never eat the same meal twice. Very rewarding.

    I think your point about how addictive substances and junk food are similar in being poisonous and inspiring lust but having nasty aspects going down or afterwards is well taken.

    The links between addiction and eating disorders are relevant. Anecdotally, I've seen how many people (especially women) experience both. Perhaps a genetic link?

    When I was a kid in school in England our teachers used to say quite unscientifically to us that the reason why people ate too much when eating junk food was that it contained less nutrients, and that the body felt cheated and one would keep scarfing it in a vain search for the calcium/protein/vitamins whatever one actually needed. We weren't focussed then on the idea that paleo types might have been primed to go for sweets so as to eat vitamin containing fruits.

  5. Hah, you junkie you.

    Chocolate, especially dark chocolate or raw cacao is a flat-out drug. Inhibit or overwhelm the enzymes that limit/prevent certain molecules from getting into your system and you're off to the races bruddah.

    FWIW I keep one pound bars of 65% dark chocolate in the pantry and can limit myself to one, (1) square......but give me a bag of potato chips and I'll eat them all. I always have chocolate, I never buy chips.

    Also people's reactions to spicy foods are heavily involved in reward/stimulation cycles. Drug use is universal.

  6. My thoughts are similar to Stanton's. "Reward" and "addiction" seem like non-scientific terms in this context. They don't describe what's going on biochemically. Wouldn't it be just as easy to say that the bland food simply fixed hormonal (leptin and insulin) signaling? Then do the hard part of scientifically determining what it is about those different foods that caused a different metabolic response. As you point out Dr. Deans, those terms can mean different things to different people.

    If it is the case that 75-90% of alcoholics are hypoglycemic, then it seems like that's the condition that should be treated, not made up term like "alcoholism" that simply restates the problem. Those ad hoc terms seem to get thrown around when the fundamental problem starts getting a bit too difficult. Or, as a rocket scientist friend of mine likes to say, "People will start ignoring variables until they understand the problem." The reason Sugar: The Bitter Truth was so compelling was because Dr. Lustig went into the dirty biochemical details. I thought Kessler glossed over the biochemical and hormonal details, at least in this Authors@Google talk. He spent the first half hour talking about dopamine as if it was completely independent of any of the other hormones.

  7. Js290 and J. Stanton - The issue here is that, clinically and in research, all psychiatric disorders are defined by a recipe list of phenotypes. This "atheoretical" standard is actually *deliberate* and proscribed starting with the DSMIII back in 1980. The standard was adapted at the time as the pathology of these diseases in the brain were unknown, and there was a lot of squabbling between the "biologic" and "psychologic" crowds as to the causes of the disorders. Thus, the powers-that-be determined we would leave "cause" out of the definition.

    Of course this proscription leads to a lot of frustration - and one could argue that all the diagnoses then are circular and meaningless. I am fairly used to the frustration at this point - however, I do see a scientific use for evaluating phenotypes for similar underlying pathologies, which is what I attempted to do in this blog post between addiction (more properly defined as substance dependence, more properly defined still as etoh dependence, opiate dependence, etc) and the phenotype of binge eating, including some issues (such as the fact that we binge on distasteful things, for the most part) that seem to belie the "food reward" hypothesis of obesity a bit (if we are indeed comparing apples to apples, which we may not be).

    I disagree with you that these phenotypes are meaningless (or uninteresting) - The term "substance dependence" it is not the same as saying alcoholics are alcoholics because they drink more alcohol. And the "food reward" term when applied to the research and inflammation in the brain gives us a lot of information as to pathology - which then gives us clues as to the holistic physiologic picture -

    "Hypoglycemia" is a phenotype as well - what makes one hypoglycemic? Low cortisol? Spikes of insulin? Pregnancy hormones?

    Back to the psychiatric diagnosis picture and how frustrating it can be - I can name three separate diagnoses with three separate phenotypes - dysthymia, major depressive disorder, and generalized anxiety disorder - that have essentially identical genetics and respond exactly the same to treatment, suggesting loosely that the three diagnoses are probably due to the same pathology. And yet the way the money for research flows and how the FDA approval process for treatments is based on the DSMIV criteria, it is a bit difficult to study the diagnoses together.

    So, once again, we are all frustrated, but sometimes understanding the reasoning and the history can help us put that aside and try to cope with and analyze the data we do have.

    And Js290 - I do plan to go more specifically into etoh dependence and hypoglycemia.

  8. Whenever I feel bad, stressed out or tired I feel like one of Pavlov's dogs. The brain screams for chocolate or something sweet and fatty. I've found out that eating some fat eases the urge for such foods, and I suspect a shortage of metabolizable fuel might be involved, but eating fat or bland food does not completely remove the cravings for something hyper palatable. Time does, however. I would be surprised if food reward does not play a part in causing obesity. But I have seen little to suggest that it plays a significant part and I would not be comfortable basing a weight loss strategy on it. Still, a very interesting subject.

  9. Dr. Deans:

    I'm absolutely not contending that "reward" and "addiction" are unscientific terms, nor that it's not useful to classify disorders by phenotype. Research has to start with a phenotype, because the underlying etiology isn't yet understood. The first step to solving a problem is to define it.

    What I'm saying is that defining "food reward" as a cause of obesity is a first step that's been taken by common sense a long time ago. Everyone understands that some foods seem to promote addictive overeating, and the dopamine reward (and its diminishment with increased obesity) of such foods is also understood.

    The question then becomes "Why?" The discussion so far seems to simply assume a concept called "palatability" is responsible, and that we all intuitively understand which foods are palatable and which are not. But there are still multiple problems here: first, without defining what makes food "palatable", we haven't done anything but restate the problem. (It's just like saying "alcohol reward" is created by "drinkability".)

    Second, and most importantly, there are plenty of extremely palatable foods that don't promote addictive overeating. That is the conundrum I'm addressing in my article.

    In other words: I absolutely believe that the concept of "food reward" has merit. I also believe that the discussion so far is handwaving all of the interesting parts.


  10. I would argue that binge eating is a related, albeit separate issue from garden variety obesity.

    I never binged, never had that urge, and ended up 280 pounds by the time I was 20.

    Binge eating does seem to be more specifically a mental problem, perhaps related to metabolic ones, but mental specifically. Even if we assume there is no specific "brain disorder" that causes binging, it seems clear to me that most binge eaters have at least a conditioned psychological aversion to food. This is why they binge. They try to restrict or moderate their intake during the day only to gorge on it later in a binge. Even if we assume there is no neurobiology causing binging the way there is causing heroin use, we can't argue or deny that there is a clear cut psychological food aversion found in binge eaters. They love and they hate food.

    When I was fat and growing fatter I was apathetic and complacent about my weight and eating. This is why I did not binge. I allowed myself to eat as much as I wanted and was hungry for. When you don't care at all about your weight and view it as a neutral phenomenon outside of your control, you can't possibly feel angst about eating and attempt to control it (only to fail and binge eventually). When there is no psychological food aversion, there will be no attempt to control food, thus there can be no binge.

    For myself and fat people like myself, my obesity was nothing to do with food palatability and everything to do with glucose and insulin. I was cured the day I found low carb. The day I went on a low carb diet I announced to my family I would be thin, because I was cured. I knew I was cured because the change in my body was obvious and extreme and I could not keep weight on if I TRIED, once I got off the glucose and my endocrine system got in line.

    They laughed at me. Who's laughing now, in my size zero jeans?

  11. john -
    I don't want to get into this again but I don't think leptin resistance causes obesity. If it did, my story could not have happened. Within days of going low carb, I was nauseated with no appetite, hemorrhaging body fat (it felt like my body was working properly for the first time ever - it felt like I could finally ACCESS the food stored on my body whereas previously I could not, it was locked in my fat cells), with a radical change in my mood, with a complete amelioration of all signs of the endocrine disorders I had.

    If leptin resistance was my problem, low carb high carb none would have helped. I would have remained fat and hungry.

    Also it is worth mentioning all garden variety obese people are afflicted with precocious puberty and HYPERgonadism , which is to be expected when leptin signaling is high and insulin is also high. Leptin deficient/resistant people will experience hypogonadism and delayed or absent puberty. Leptin plays a central role in fertility as well as preventing starvation (they are related, you know).

    Anorexics are not resistant to leptin, FYI. They just make almost no leptin at all due to atrophy of body fat and very low insulin/very low glucose metabolism. These factors suppress leptin to nothingness.

    Fat people, also, do not have high rT3. Fat people have hyperactivity of the thyroid with high levels of fT3 which is to be expected when insulin and leptin and glucose are high.

    I believe food reward only figures into obesity when the metabolic disorder for obesity is already in progress. Speaking personally, while afflicted with runway insulin levels, the palatability of my diet certainly affected how fat I became... but only in the context of hyperinsulinemia. Now that I know what I know, I can eat as tasty as I want as much as I want; as long as my insulin is balanced I am capable of intrinsic weight regulation.

  12. @J. Stanton - good point, that opening line to GCBC was hard hitting and still holds true here. "Food reward" explains nothing. Why is food hyper rewarding to some people? Why don't these people ever experience nausea and disgust from fullness?

    Thin people, in my experience, tend to love and enjoy food more than fat people. However what makes thin people different is that eventually they feel FULL. When thin people are asked to over eat , they feel nausea and disgust and no longer view their beloved food as appetizing.

    The reason fat people get fat, is because none of that happens for them. I know, I was there. No matter how much they eat, they never feel full, never feel satisfied, NEVER feel nausea.

    Why doesn't it happen?
    Low dopaminergic tone is one critical pathophysiological process in obesity.
    Dopamine is a major metabolic regulator. A key feature of garden variety obesity, as well as hibernation, is a functional downregulation of dopamine receptors. Dopamine binding completely orients cell-level metabolism around in favor of glucose metabolism. This prevents hyperinsulinemia. Peripheral dopamine binding suppresses insulin production from the pancreas, preventing hypoglycemia after eating, and prenting lipogenesis. When dopamine is blocked, or when dopamine receptors are functionally downregulated during obesity (glucose excess results in the downregulation), the cells shift to a preference for fat metabolism, which paradoxically induces glucose intolerance and hyperinsulinemia and fat gain. Low dopamine also reduces psychomotor activity (energy-sparing) and promotes sleepiness/inattentiveness, another common complaint in obesity as well as in hibernation.

    When you give dopamine blockers to lean metabolically healthy mentally ill, they phenotypically resemble mentally healthy metabolically ill people. They have crap glucose tolerance, gain body fat, move less, sleep more, lose motivation to the point of depression. THey enter a mini hibernation. They look like I used to look before I figured out that glucose triggered this horrible syndrome.

    When you take a PET scan of an obese person's dopamine binding, it is non-existant. This is rapidly corrected upon food restriction, suggesting the dopamine receptor downregulation is not pathological but rather a functional innate trait, almost a response to food, or certain foods.

  13. I believe garden variety obesity is nothing more than an evolutionarily conserved "hibernation" tendency. Much like seasonal affective disorder or bipolar spectrum disorders, the tendency to respond to glucose in this way represents a form of preemptive detection and adaptation to seasonal trends. Carbohydrate is a powerful seasonal indicator. Carbohydrate is plentiful before the lean winter months, and certain humans have evolved genetic traits which capitalize on it by down regulating dopamine receptors in response to high glucose diet. In a logical environment it works out, the carbohydrate is seasonal, and come winter the body fat is lost and spring breaks and it terminates.

    This is why obesity is typically found in NAs, africans, and others who come from recent hunter gatherer lineage where subtle low grade changes in the season meant big impact on nutrient availability. It is not found in asians or most europeans quite as frequently due to a long history of agriculture, which to some degree obliterated the impact of seasonal trends on nutrient availability (and definitely obliterated the importance of dietary glucose as an indicator of season).

    I have observed, throughout my shifts in physiology over the yeras, that sensitivity to nausea is a major, major indicator of my mood and metabolic state. When I am motionless, immobile, dim in the mind, sleeping easily and excessively, given to appetite and gaining fat I am very rarely nauseated, and find it very difficult to become nauseated. On the othe rhand, when I am brimming with energy, lively and excited in the mind, difficult to sleep, given to low appetite and weight loss, I am VERY EASILY nauseated.

    During my research I discovered that dopamine is a major regulator of nausea, and this seems related to its regulation of metabolism and appetite. Antiemetics are dopamine blockers, typically. Reglan is a dopamine blocker. Reglan can double as an antipsychotic. Reglan can cause EPS, tardive diskinesia (irreversible upregulation of certain dopamine receptor subtypes in certain parts of the brain, caused by a hard block of dopamine receptors). Some antiemetics also block serotonin, as serotonin also regulates nausea, but dopamine more so.

    IN obesity, or at least some subtypes of obesity, we must accept that shifts in CNS dopamine mediate it.

  14. js290
    While I can't say I've read the research on alcoholics and hypoglycemia, I can say as a person who is sensitive to hypoglycemia that alcohol itself is the stimulus that will cause hypoglycemia. Whenever I drink I EXPECT a hypo after my liver metabolizes the stuff, and the reason is that alcohol is metabolized preferentially and suppresses liver gluconeogenesis. This will induce hypoglycemia assuming you are sensitive to develop it, as I am.

    So when saying 90% of alcoholics are hypoglycemic we must consider that using alcohol is sort of like taking a drug like metformin - alcohol suppresses blood glucose. Low sugar is an expected consequence, unless you are diabetic... and this is why diabetics are advised to drink moderate alcohol, it helps their sugar like metformin.

    Speaking as a hypoglycemic, I hate drinking alcohol and it is hard for me to even enjoy it because I know I will be SHAKING LIKE CRAZY AND LIT UP FROM EPINEPHRINE for the rest of the night and maybe the next day.
    I don't think any truly hypoglycemic person would drink alcohol as a solution, it makes it much more noticeably worse.

  15. JS - agree I want to see Stephan's neurochemistry - he hints that post is coming.

    Woo - yes, a weakness of my argument is that most obese people are not binge eaters. However, I feel when discussing the "food reward" issue it is a fair extreme to analyze, related as you say. At least in rats bingeing does not lead to wt gain unless you combine shortening + sweet.

    I don't think dopamine blockade is the major reason many antipsychotics cause weight gain, though of course they do stop nausea (and hiccups). It seems to be a histamine effect for most of the atypicals, and also (through different mechanisms, depending on the antipsychotic) GLUT transporter regulation. However, wellbutrin, dopamine activator (indirectly) does cause nausea and weight loss BUT the tricyclics and MAOIs will also increase dopamine and they all cause weight gain.

  16. FHA in P- my understanding is that on A bland diet one will automatically consume less. There is no altering of the laws of thermodynamics jere.

    Woo - one more anti-dopamine thought - stimulants such as adder all will cause weight loss for three months, then no change in overall weight, otherwise stimulants would be used or FDA approved for weight loss (they are not). Instead, serotonin drugs (phentermine, meridia) are used for weight loss - and cause valve problems. In fact the only truly useful drug I know for weight loss besides wellbutrin is topamax, and I don't know that anyone knows why that one works.

  17. On almost all the boards discussing food rewards, the bulk of the contributors are conflating (1) 'taste' with 'palatability', as well as conflating (2) 'liking' food with 'wanting' food.

    'Taste' does not equal 'palatable'; high taste foods (like fruits) are not necessarily hyper-palatable foods (like snickers bars). Taste is merely a simple descriptor of the mouth-centred perception of flavour; palatability is a 'meta' term representing the affective response of the human brain and body to things that include taste (but also include texture, sugar content, fat content, calorie density, memory/emotive activation, food appearance, food packaging etc.).

    Bottom line; taste is only one of the myriad of factors that determine if a food affects a subject as being hyper palatable or not.

    And this really matters....


    'Liking' a food does not make you necessarily 'want' a food, and it is the 'wanting' of foods that typifies the chronic overeating that leads to obesity. Kate Wassum ( ) at UCLA shows that liking foods is dissociable from wanting foods.

    This really, really matters...

    Because it shows that eating a 'bland' or 'tasteless' diet is missing the point.

    The point is: we are free to eat a tasty, enjoyable diet that we really really 'like' long as it controls for the hyper-palatable foods that we really really 'want'.

    Just because snickers bars aren't a great idea, this doesn't mean we're doomed to a diet of boiled rice and kelp.

    There's a world of choices that fall between hyper-palatable and bland foods.


  18. Dr Deans -
    The role dopamine plays in the hibernation response is well studied - D2 receptor agonists will prevent hibernating animals from shifting physiology toward hibernation. IT's worth noting, and is probably NOT incidental, that the phenotype of an animal preparing for hibernation is almost exactly like that of an obese person. They develop glucose intolerance, eat more, gain body fat even if they are prevented from eating more, move a lot less (apathy/"depression"). Obese people, such as myself, generally find weight gain is worse in the fall and winter. Evidence does seem to suggest at least some types of obesity may be a functional form of seasonal adaptation which can be corrected by controlling the environmental factors which trigger it.

    The way dopamine affects cell level metabolism is also demonstrated; without adequate dopamine signaling the cells use fatty acids for energy, refusing glucose. Dopamine blockade plays a significant role in energy using defects that later lead to diabetes and obesity, this has been researched and shown.

    Histamine certainly plays a role in weight gain (e.g. low dose seroquel) but most of the metabolic consequences from psych drugs are mediated by dopamine. You don't get diabetes from 25mg of seroquel, even though the histamine effects are significant. You get diabetes from >300mg of seroquel, when you are blocking d2 receptors. Also, serotonin blockade of many atypicals influences glucose tolerance negatively as well. Serotonin is very influential in glucose tolerance, not just dopamine.

    I've had the pleasure of taking low dose seroquel a few times. It certainly made me quite hungry, but only after taking it; it had no affect on my metabolism or weight other than the immediate appetite increase which was relatively short lived.
    Are stimulants which augments not just serotonin, but catecholamines, like dopamine and norepinephrine and epinephrine. I do not understand why you are calling it serotonergic, it has more in common with wellbutrin than a serotonin drug. The primary neurotransmitter effected is norepinephrine, but amphetamines are primarily catecholaminergic. SSRIs cause weight gain and when the person is very sensitive may even have side effects like antipyschotics (e.g. hyperprolactinemia, EPS or akathesia) because an excessive serotonin level suppresses normal dopamine activity.

  19. The reason catecholaminergic stimulants (or wellbutrin, or any legal drug) do not correct obesity is because the brain adapts to them and downregulates receptors pretty quickly. Anyone with a caffeine habit can attest to that, any stimulant works very very temporarily before poop out and tolerance. This is also why they are ineffective for depression and lack of motivation/attention most of the time. Unless you are mainlining methamphetamine or another super powerful stimulant... weak crap like caffeine, adderall, or amphetamine is not going to be enough to correct the severe dopamine insensitivity of obesity. The only way to do it, is to do it the evolutionarily logical way - you need to stop eating glucose stat and then your brain will make dopamine receptors like it should. Once off the glucose your body will no longer think it's preparing for hibernation and viola you will feel normally think normally and regulate body weight normally. Or at least, a significant proportion of obese people will.

    TCAs, should be noted, have no effect on dopamine, whereas amphetamines and wellbutrin DO have a strong effect on dopamine. TCAs cause weight gain because they are not dopaminergic, and they are antihistamine as well. Anything that augments dopamine will always lead to weight control or loss - all weight loss drugs are dopaminergic,and TCAs are not. Anything antihistimine will augment appetite, no weight control drugs are antihistamines.

    Fat people are fat not because of a catecholamine drug deficiency, they are fat because they hav ea genetic profile which goes into a semi-hibernation when glucose levels are elevated in the diet. YOu can give catecholamine drugs like amphetamines, or you could simply drop the starch and sugar so that the brain makes neurotransmitter receptors normally again. No drug will work for fat people long term, unless it addresses the functional neurotransmitter receptor downregulation which occurs in response to dietary glucose (i.e overcomes a stable functional genetic trait).

    You have to do some heavy duty stuff like crystal meth to even begin to touch that, assuming you are an obese person with nil dopaminergic tone. NO ONE stays fat on crystal meth, EVERYONE becomes cracked out and emaciated. Before they go insane and stop sleeping and lose their teeth of course.

    Note, food restricted / thin people are hypersensitive to stimulants for this reason. Heavy people have told me that they notice thin people drink a lot of coffee. I fit that profile. Thin people drink a lot of coffee not because we are trying to suppress our appetites, but because we don't have particularly high appetites (because our brain is sensitive to the dopamine it makes) and we are supersensitive to caffeine for this same reason... whereas fat people are not. Fat people are hungry all the time and have a poor response to stimulants due to central insensitivity.

  20. Topamax does cause weight loss, mechanism of action is unclear, but people report that it nixes appetite a lot. This is interesting as many antiepileptics promote weight gain and metabolic dysfunction (such as the heinous depakote).

    It seems to also help in "smoking cessation" and anything that helps in smoking cessation is almost always dopaminergic to some capacity. It's highly unlikely that it increases dopamine levels in the brain since dopamine lowers the seizure threshhold (topamax does the opposite) but it is not unreasonable to assume it may stimulate dopamine activity in very specific brain region(s), which then would contribute to its capacity to help with smoking cessation as well as hunger/appetite leading to weight loss.

  21. Included in these obesity formulation we might also consider the intensity of the reward stimulus. Just as powdered cocaine is furiously addictive while coca leaf chewers grind away at a stable rate for fifty years we might consider that our technological advantages in food availability and preparation allow us to slam our body into dangerous reward overloads.

    Something as simple as how much food we prepare in a batch or whether we have ready-to-eat foods other than fruits and vegetables around might allow us to time-compress food rewards into the addiction zone. Even the usual habit of preparing multi-course meals for simultaneous service might be the overload stimulus. if we prepared and ate the peas and then stood up to cook the steak might we eat less?

  22. Emily, if you haven't yet looked at Lustig's "Childhood obesity: behavioral aberration
    or biochemical drive? Reinterpreting the
    First Law of Thermodynamics" you should. This review gives a nice tidy look at food reward and its contribution to the obesity epidemic (from the author's point of view).

    Glad you read Kessler's book. It was an eye-opener to me. The main weakness of his argument, and the book in general, is that it is devoid of any physiology, devoid of any mechanistic explanations. Knowing my "food" weaknesses, I did buy into the fat+sugar bit, though. Give me a tub of full fat Greek yogurt and I'll eat a decent portion. Add honey to it and it's all gone.

    Great article, btw.

  23. Woo - I'm rather sorry I brought the psychotropics into it because the complications are too profound - TCAs can activate dopamine indirectly via NE, some more than others, but I agree the obesity contribution is due to anticholinergic stuff... ultimately obesity is multifactorial - genes, environment, infections (adenovirus) stress, sleep - like every other chronic disease. I think paleo diets have the potential of a cure more than anything, staring off on the low carb range... Have they studied leptin as an adjunct for weight loss? Surely they have... Though I'm not familiar with the weight loss/leptin literature


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