Our drives are largely governed by two small primitive brain structures, the hypothalamus and the amygdala – shown in red in the drawing at right.  Remarkably, these two tiny structures are respectively the size of a pea and an almond — representing less than 1% of the brain’s three pounds of neural matter. Together, they constitute the control center of the paleomammalian brain–the “limbic” brain that governs our basic urges and desires as well as our homeostatic “set points” for temperature, sleep, body fat and behavioral urges like sex drive and aggression.

You can attempt to change your behavior by conscious determination and cognitive therapies.  But most attempts at intentional change are temporary and are doomed to fail in the long term because they are strongly resisted by powerful homeostatic processes encoded in our limbic brain.  Modern medicine recognizes the importance of homeostatic drives, and has developed pharmaceuticals to override them with diet pills, sleeping pills and antidepressants.  In fact, these medications do shift the balance of neurotransmitters and neural activity — at least in the short term.  But such chemical interventions are short-sighted “crutches” that promote dependency and come with side effects.  Often they exhibit  a “tolerance” effect: the brain’s control system fights back and weakens the impact of the medication.  To maintain the benefit, doses are increased, but this strategy may not always work.

This article will explain how the hypothalamus and amygdala contribute to the regulation of basic drives like eating, sleeping and sexuality, and how the amygdala can actually override the hypothalamus by enhancing the reward value of foods and other stimuli. (As I will explain, however, my take on “food reward” is different from that of Stephan Guyenet and other advocates of the Food Reward Hypothesis). This dual-control model can help explain anomalies such as obesity, addiction, and disordered sleep.

Finally,  I will provide suggestions on effective and natural ways to re-program the hypothalamus and amygdala and change your homeostatic set points, using the principle of hormesis.

Hormesis. Readers of this blog are familiar with hormesis:  a biological process whereby a beneficial effect (improved health, stress tolerance, growth or longevity) results from exposure to judicious doses of an agent that is otherwise detrimental at higher doses.  The many examples of homesis we’ve discussed on this blog involve adaptations that roughly fall into three categories.  The first two categories are quite well-known:

Structural adaptations to organs and tissues:

• Muscular growth, from weight lifting
• Adaptations of the foot and leg, from barefoot running
• Reversal of myopia, from use of anti-corrective lenses
• Other examples: calluses, suntanning

Defensive adaptations against foreign subtances:

• Immunotherapy to overcome allergies
• Endogenous defenses against oxidants and “xenobiotic” toxins

The third category is perhaps a less well recognized form of hormesis:

 ”Psycho-metabolic” adaptations:

• Hormonal and enzymatic adaptations to caloric restriction and fasting
• Psychological and weight loss benefits of cold showers
• Cue exposure therapy to overcome addictions
• Sleep restriction therapy to counteract insomnia

Psycho-metabolic adaptations. Let’s now expand upon this third category of adaptations, focusing on how certain types of stimulus or “stress” can bring about long term changes within the brain’s control system — the hypothalamus and amygdala.  These adaptations can induce broad sets of changes to your metabolism and psychological functioning.   These changes are long term adaptations — to be distinguished from short term or “artificial” changes that can temporarily induce weight loss, boost metabolism, energy level, wakefulness, or sex drive.   A true change in “set point” requires a sustainable physiological change that is reflected in real alterations in neuron density or receptor sensitivity within the brain.  In turn, these changes to the brain result in systemic changes elsewhere in the body.

In previous posts, I’ve touched upon a few topics that relate to the general thesis of psycho-metabolic adaptations that involve changes to the brain:

1. In “Change your receptors, change your set point“, I presented evidence that individuals suffering from obesity, addiction and depression have in common a down-regulation (reduction in the number or sensitivity) of dopamine receptors. In depression, receptors for other neurotransmitters such as serotonin are also down-regulated, a problem that can actually be made worse by chronic use of SSRI antidepressants.  The article also summarized research indicating that intense exercise, caloric restriction and intermittent fasting can up-regulate dopamine receptors and thereby provide a sustainable treatment for certain types of obesity, addiction and depression.
2. In  ”Obesity starts in the brain“, I outlined the Hypothalamic Hypothesis, a brain-centric analysis of obesity.  I argued that there are two different types of obesity–intra-abdominal and subcutaneous obesity–and that these conditions respectively result from  impairments to the insulin sensitivity or leptin sensitivity of a specific part of the hypothalamus — the arcuate nucleus.  Furthermore, it is the hypothalamic impairments that are primary; for example, insulin resistance starts in the brain and later spreads to the liver and muscles.  The article pointed to specific dietary and inflammatory factors that can improve hypothalamic sensitivity to these hormones and reverse obesity.

I will now build upon the Hypothalamic Hypothesis to account for the influence of the amygdala, to consider how the limbic system governs for drives other than eating, and to propose more generally how we can influence the brain’s control system.

The limbic system. Think about this:  By weight, about 85% of the human brain is the elaborate cerebral cortex, devoted to complex perceptual and conceptual processing and executive function.  In contrast, only a tiny piece of the brain is responsible for the full gamut of motivational drives and emotions, and for maintaining the balance of homeostatic functions like metabolism, body temperature, sleep and energy level.  The simultaneous management of all of these diverse functions is tightly packed into two nut-sized structures–evidently without getting signals crossed! When you think about it, this fact is quite astonishing.  It baffles me that, despite great popular interest in neuroscience, there has been so little commentary about this striking fact.

You can think of the the massive cortex as merely an elaborate pattern recognition system wrapped around the limbic brain.  The cortex’s pattern recognition system has evolved to improve the quality of information being fed to the tiny thermostatic hypothalamus and amygdala.  While the cortex gives us a huge advantage over other animals in analyzing our environment, we seem not to much real control over basic drives like eating and sleeping.  Despite the evolutionary achievement of “rationality”, we humans remain to a large extent at the mercy of our basic animal drives and emotions.

Things are not so bleak, however, once we recognize what makes the limbic brain tick.  While we may not have direct volitional control over the limbic system, there are actions we can take to influence the balance of neural forces within the hypothalamus and amygdala. Over time, we can literally reprogram our psycho-metabolic control systems.

But first a little anatomy.   And I’ll try to keep things simple.  The point of this interlude is not to teach anatomy, but rather to highlight a few key parts of the limbic control system and how they function. I’ve borrowed much of the following discussion from the excellent and incisive monograph, The Limbic System, by Rhawn Joseph, much of which is also contained in Chapter 4 of his online Brain e-book.

The figure below provides a “macro” view of the major parts of the limbic system.  Located at the center of the brain, perched atop the brainstem, the limbic system includes not only the hypothalamus and amygdala, but other structures such as the hippocampus, cingulate gyrus, pituitary gland.  But particularly note that the amygdala is connected tightly by numerous nerve bundles to the hypothalamus.  The amygdala acts directly on the hypothalamus to control hypothalamic drives, and conversely, the hypothalamus “uses” the amygdala (and to some extent the septum) as a window on the world to satisfy its drives by selectively searching out appropriate foods, potential mates, and sleep and exercise opportunities.

Furthermore, notice that the amygdala is closely connected to the olfactory bulb, and mediates its connections to the hypothalamus.  As Joseph notes, “The hypothalamus is exceedingly responsive to olfactory (and pheromonal) input. Perhaps reflecting this partial and putative olfactory origin is the fact that this structure utilizes chemical (hormonal, humoral) molecules to communicate with other areas of the brain, and reacts to these same molecules as well as olfactory cues, including those directly related to sexual status.”  We will come back to the under appreciated importance of olfactory cues in the limbic system’s control of basic drives, particularly appetite and sexual/social attraction.

For present purposes, there are four important points to understand about the actions of the hypothalamus and the amygdala:

1. The hypothalamus is purely reactive. The hypothalamus regulates drives, but is almost totally “blind” to the outside world.  It is inwardly focused and responds reflexively.  It has no memory and acts “in the moment”.   According to Joseph, the hypothalamus is the physical embodiment of the Freudian id:

Emotional functioning at the level of the hypothalamus is not only quite limited and primitive, it is also largely reflexive… Emotions elicited by the hypothalamus are largely undirected, short-lived, being triggered reflexively and without concern or understanding regarding consequences; that is, unless chronically stressed or aroused. Nevertheless, direct contact with the real world is quite limited and almost entirely indirect as the hypothalamus is largely concerned with the internal environment of the organism. Although it receives and responds to light, it cannot “see”. It has no sense of morals, danger, values, logic, etc., and cannot feel or express love or hate. Although quite powerful, hypothalamic emotions are largely undifferentiated, consisting of feelings of pleasure, unpleasure, rage, hunger, thirst, etc….it tends to serve what Freud (1911) has described as the pleasure principle. Functionally isolated, the hypothalamus at birth has no way of reducing tension of mobilizing the organism for any form of effective action. It is helpless. When tensions associated with immediate needs (e.g. hunger or thirst) become unpleasant the only response available to the hypothalamus is to cry and make rage-like vocalization. When satiated, the hypothalamus can only respond with a feeling state suggesting pleasure or at least quiescence.

2. The hypothalamus operates through a hierarchy of channels.  The hypothalamus receives information about the state of the organism, and in turn sends “commands”,  through three main channels:

• The bloodstream. Many signals are exchanged through the relatively porous blood-brain barrier.  For example, as discussed in my previous post on obesity, the hypothalamus receives and integrates a range of signals about short term nutrient status (glucose and fatty acids), gut signals (ghrelin, PYY and CCK) and longer term energy storage  (hormones like insulin, glucagon, leptin and adiponectin).   The blood also carries similar signals regarding body temperature, wakefulness and sleep, and state of readiness for action. And the hypothalamus activates the section of neuroendocrine activators via other glands like the pituitary, thyroid and adrenal glands.
• Nerve fibers –”afferents” and “efferents”.  Certain communication is done via nerve fibers. For example, appetite cues are provided from the nose via the olfactory bulb and from the gut via the vagus nerve.  Body temperature cues are provided from remote thermoreceptors.  The sleep-wake cycle is calibrated by neural inputs from the suprachiasmatic nucleus (SCN), which responds to dark and light cycles.  And conversely, the hypothalamus uses efferent nerves to remotely regulate adrenal glands and digestive organs.
• Higher order inputs.  The above chemical and neural inputs can be modulated or overridden by “emotional” interpretation of perceptual and cognitive inputs.  This is is where the amygdala comes in.

3. The amygdala is the “handmaiden” of the hypothalamus.  It serves as the emotional eyes and ears for the hypothalamus by translating the input of the senses and the great pattern recognition capability of the higher cortex into emotional responses that feed into the hypothalamus.  Going beyond the undifferentiated, spur-of-the moment emotional drives of the hypothalamus, the amygdala provides a highly selective response to specific and often complex sensory stimuli.  As Joseph explains:

In contrast to the primitive hypothalamus, the more recently developed amygdala (the “almond”) is preeminent in the control and mediation of all higher order emotional and motivational activities. Via it’s rich interconnections with various neocortical and subcortical regions, amygdaloid neurons are able to monitor and abstract from the sensory array stimuli that are of motivational significance to the organism. This includes the ability to discern and express even subtle social-emotional nuances such as friendliness, fear, love, affection, distruct, anger, etc., and at a more basic level, determine if something might be good to eat.  In fact, amygdaloid neurons respond selectively to the flavor of certain preferred foods, as well as to the sight or sound of something that might be especially desirable to eat  including even the sight of drugs that induce extreme pleasure…Belying its involvement in emotion, including the pleasure associated with cocaine usage, is the unique chemical anatomy of the amygdala, which is rich in a variety of neuropetides including enkephalins and beta-endorphins as well as opiate receptors. In fact, of all brain regions, the greates concentration of opiate receptors is found within the human amygdala.

Beyond appetite, the amygdala also provides a selective filter on sensory cues related to other drives such as sociality and sexual attractiveness.  Of significant note, the amygdala is the arbiter of very specific social cues such as facial recognition:

The amygdala is exceedingly responsive to social and emotional stimuli as conveyed vocally, through touch, sight, and via the expressions of the face . In fact, the amygdala, as well as the overlying (and partly coextensive) temporal lobe, contains neurons which respond selectively to smiles and to the eyes, and which can differentiate between male and female faces and the emotions they convey. For example, the left amygdala acts to discriminate the direction of another person’s gaze, whereas the right amygdala becomes activated while making eye-to-eye contact …Moreover, the normal human amygdala typically responds to frightened faces by altering its activity, whereas injury to the amygdala disrupts the ability to recognize faces. With bilateral destruction, emotional speech production and the capacity to respond appropriately to social emotionally stimuli is abolished.

Maybe this explains why Seth Roberts observation that looking at faces in the morning makes people happy–a simple anti depression therapy!

Joseph also notes that “The relationship between hypothalamus and amygdala is bidirectional.  The amygdala interprets sensory information and emotions and passes these inputs on to the hypothalamus to initiate drives. And when a drive like hunger or sex emerges, the amygdala helps out by surveying the environment for suitable choices of food or potential sexual partners.”

4. The hypothalamus and amygdala  are composed of opposing sets of neural clusters or “nuclei”.   These pairs of neural clusters act in an oscillating ying-and-yang fashion to achieve homeostasis. In both the hypothalamus and amygdala, the external or lateral nuclei activate the parasympathetic nervous system, associated with hunger and digestion, pleasure, relaxation and sexual arousal.  In the case of appetite, stimulation of neurons in the lateral hypothalamus (LH) increases  appetite, releases serotonin and dopamine, and activates anabolic storage of  glucose and fatty acids,  In opposition to the lateral nuclei, internal or “medial” nuclei activate the sympathetic (“fight or flight”) nervous system, which readies the organism for action, increases heart rate, suppresses appetite and sexual desire, stimulates release of acetylcholine and norepinephrine, and activates catabolic mobilization of nutrients such as fat or glycogen.  Stimulation of the medial nuclei are also associated with “aversive” non-pleasurable sensation.

Similar pairings of opposing limbic nuclei exist for neurons that control thirst, body temperature, the sleep/wake cycle, or activate social or sexual arousal.

The amygdala has a parallel structure to that of the hypothalamus, which allows direct two-way communication between them.   As Joseph notes:

Moreover, through the massive interconnections maintained with the lateral and medial (ventromedial) hypothalamus, the amygdala is able to act directly on this structure, driving the hypothalamus, so to speak, and thus tapping into its emotional reserviour so that its ends may be met. Indeed, it is able to modulate hypothalamic activity through inhibitory and excitatory projections to this structure. Direct stimulation of the basolateral amygdala and the ventral amydalofugal pathway excites the principle neurons of the medial hypothalamus. By contrast, stimulation of the medial (ventro-medial) amygdala and the stria terminalis pathway, inhibits these same hypothalamic neurons. Hence, whereas the lateral amydala exerts excitatory influences on the hypothalamus, the medial amygdala exerts inhibitory influences, and can thus control, or at least exert excitatory/inhibitory and thus modulatory influences on hunger, thirst, sexual arousal, rage, etc., as well as hormonal, endocrine, and other functions associated with the hypothalamic nuclues. Indeed, the amygdala can be likened to the chief executive of the limbic system and weilds enormous power via its control over the hypothalamus.

Similar sets of paired hypothalamic and amydaloid nuclei govern the balances that control thirst, body temperature, sleep and sex drive.  For example, osmoreceptors that monitor the concentration of salt ions in blood control thirst, and respond by adjusting the hormone vasopressin to regulate water retention by the kidney. Thermoceptors in the body and hypothalamus activate different nuclei in the hypothalamus.

Generalized versus conditioned desires. By serving as the “interpreter” that provides higher-level emotive “meaning” to raw sensory inputs, the amygdala plays a prominent role in learning and laying down reward circuitry.  In effect, it turns complex sensory inputs into cues that the hypothalamus can act upon by establishing Pavlovian circuits that automate the way your basic drives respond to the external environment and even your thoughts.  This applies to both attractive (stimulatory) and aversive (inhibitory) stimuli. As mentioned above, the reward circuitry utilizes a high concentration of dopaminergic neurons to reinforce powerful learned responses of the hypothalamus to sensory cues and thought patterns.

While the hypothalamus activates generalized drives and provides hard-wired low-level responses to universal and fairly general cues, the amygdala provides finely tuned and highly specific learned responses that can modify or override these low level cues:

The hypothalamus gets hungry and anything will do…,but the amygdala is picky about which foods it likes or dislikes, to the point of craving a specific type of chocolate with a certain texture, or rejecting a wine with a slight off-note
The hypothalamus wants sex…but the amygdala is selective about what turns it on — down to very fine preferences regarding appearance, aroma, or even sense of humor.  It may be so selective as to be monogamous!
The hypothalamus wants to sleep… but the amygdala picks up cues about danger that can rally your alertness.

The key point is this:   The generic drives of the hypothalamus are equally powerful whether they are activated by low level chemical and nerve inputs from the blood stream or stomach nerves — or rather by higher level perceptual and emotional inputs from the amygdala.  And if the reward circuitry from the amygdala is strong enough, it can override the low level signals.   A Pavlovian response to the aroma of a juicy steak or the sight of a decadent chocolate cake can activate the hunger response and fat storage program initiated in the lateral hypothalamus, regardless of the nutritional state conveyed by blood glucose or leptin and insulin levels.  Conversely, an unappetizing meal, or an emotional shock can quickly suppress appetite or activate a state of arousal and access to energy.

The hypothalamus doesn’t know or care why it is getting hungry, sleepy or sexed up.   It matters not whether the signals are based on blood chemicals or high level emotional perception — the actions taken by the hypothalamus are identical in either case.

An aside on food reward. This dual model of direct hypothalamic regulation versus conditioned amygdaloid regulation of drives like hunger can shed some light on the recent debate about the Food Reward Hypothesis of obesity.  Stephan Guyenet has cited compelling evidence for the FRH, based on the  observation that rats fed a “cafeteria diet” of highly palatable junk food became fatter than rats fed calorically matched standard bland rat chow.  Merely adding flavor or flavor variety to the chow also resulted in fatter rats.

However, in an earlier post, “Does tasty food make us fat?“,  I argued that Guyenet’s version of the FRH suffers from two logical flaws:  First, Guyenet does not take a clear position on whether “reward” is an inherent property of foods, or rather a learned or conditioned property, relative to individual and cultural experience.  Second, while rewarding food is associated with obesity, the causal sequence can be questioned.  I think it is likely food reward is the is the consequence, not the driver of psycho-metabolic dysregulation.  Food becomes rewarding only after primary hypothalamic regulation becomes impaired, for example by the way that the particular fats and sugars in junk food desensitize hypothalamic receptors to insulin or leptin, as I described in “Obesity starts in the brain“.   Of course, once the amygdaloid food reward circuits are established, they can be expected to perpetuate an increased appetite and shift away from fat mobilization to fat storage.  But the amygdaloid reward circuit is not the primary defect — that remains the impairment to the hypothalamus.  The proof is that it is not just appetite that is impaired — it is also the metabolic consequence of a more active lateral hypothalamus and inhibited ventromedial hypothalamus.   If the hypothermic defect is repaired, the food reward circuit should extinguish.

THE BOTTOM LINE

Hormesis and the hypothalamus.   So how do we use this information?  Specifically, how do we “judiciously” apply “stress”s to re-program our limbic control system. What if we are gaining weight due to both a strong appetite and more “efficient” storage. Or what if we have trouble falling and staying asleep?  Or (more speculatively) what if we want to become more or less aggressive, or more or less sexually motivated?

In short, our understanding of the limbic system suggestions two approaches:

1.  Direct reprogramming of the hypothalamus. Every drive is regulated by a balance of stimulatory and inhibitory neurons.  By the logic of hormesis, we can stimulate the growth of one set of neurons or the other by periodically  ”starving” them of their normal stimuli, allowing a compensatory up-regulation of receptor neurons.  Often this process is slow, and the compensating adaptations may take weeks or longer — but with sustainable results. This is the reverse logic illustrated in several posts.

• “Change your receptors, change your set point”  demonstrates how exposure to uncomfortable stresses such as intermittent fasting, strenuous exercise, cold showers and the like can up-regulate dopaminergic neurons and thereby counteract conditions such as obesity, addiction and depression.  While the research cited in that article doesn’t specifically locate the dopamine neurons, , we know they have a high density in the hypothalamus, amygdala and other limbic structures, and the PET scans indicate a brain location consistent with the hypothalamus and amygdala.
• “A cure for insomnia?” describes the use of Sleep Restriction Therapy (SRT).  By forcing extended wake cycles, there is an apparent rebalancing of hypothalamic neurons in the ascending arousal system, thereby activating sleep-active neurons in the ventrolateral preoptic nucleus (VLPO) associated with the  “flip-flop switch” that produces distinct sleep-wake states.  As a result, SRT reduces the  excessive production of corticotropin-releasing factor (CRF) that is associated with many cases of insomnia.

That theory has been around the block but it is in fashion again.   In 2009, David Kessler’s book, “The End of Overeating” put forward the thesis that food in contemporary American food has been deliberately engineered–by adding fat, sugar and salt–to exploit our neurochemistry and hijack our free will.

More recently, one of the luminaries of the Paleo movement, Stephan Guyenet, has formulated his own version of this theory, in a compelling series on his Whole Health Source blog, arguing that  ”food reward” is a main driver of obesity. His prescription:  eat a bland diet. Guyenet’s talk about this at the Ancestral Health Symposium last month is the buzz of the paleosphere.

But I think the theory is wrong, for the simple reason that it too blindly takes correlation for causation. And in doing so, it gets the causal direction mostly wrong. We don’t get fat because food has become too tasty. Rather, to a large extent, it is the metabolism and dietary habits of the obese that make food taste too good to resist, leading to insatiable appetites. And the good news is that we are not consigned to blandness.  If we eat and exercise sensibly, we can eat flavorful, delicious foods and enjoy life, without packing on the pounds.

Brain chemistry. Stephan Guyenet’s series on food reward, like Kessler’s book, pins the blame for obesity largely on the increased availability of more palatable “high reward” food.

According to USDA data, Americans today eat an astonishing 425 more calories per day than they did in 1970.  That is the reason for the obesity epidemic, plain and simple.  However, that fact doesn’t tell us why we’re eating more calories, so its usefulness is limited. The increase in calorie intake has come primarily from refined carbohydrate, but even that doesn’t get us very far, because why did we decide to eat more refined carbohydrate?  Probably because of the systematic efforts of commercial food manufacturers to increase the palatability/reward value and availability of processed food.  In the last four decades, the US has become saturated with hyperpalatable/rewarding commercial and restaurant foods including fast food, soda, french fries, chips, candy and other industrial products.  I’ve seen people claim that they ate these things just as much in the 1960s and 70s, but the USDA and National Restaurant Association data show otherwise.  The qualitative changes in the US diet have been swift and profound… (A Roadmap to Obesity, August 25, 2011)

But what is it about food that makes it rewarding or not?  Guyenet suggests that food reward relates to opioid and dopamine signaling:

Feeling satisfied after eating something is not reward. If you keep eating a starch food beyond what’s appropriate, that is probably because it has too much reward/hedonic value for you. Opioid signaling, implicated in hedonic processing, shuts off satiation signals in the brain and may also increase the setpoint. Dopamine signaling, implicated in reward, can strongly influence food intake and also seems to be able to increase the set point.

In “The End of Overeating”, Kessler also emphasizes the way that “hyperpalatable” foods stimulate dopamine, opioids and other reward neurotransmitters.  To be fair, both Guyenet and Kessler acknowledge that food reward is not the only explanation for obesity.  They acknowledge the role of genetics, exercise and other factors.  But for both of them too-tasty food is the leading culprit.

The relativity of taste.  But is it really that simple?  Are some foods inherently and invariably rewarding? Do our taste buds and noses directly respond to tasty foods or foods high in fat, sugar or salt by stimulating the secretion of dopamine and opioids in the brain, turning us into addicts? Somehow, it must be more complex than that.

Seth Roberts has postulated a different explanation, in which learning plays a role. His Shangri-La Diet was derived from observations that tasty foods lead to weight gain only after repeatedly encountering the flavor and the calories together. Roberts calls this process “flavor-calorie association”.  It’s a Pavlovian conditioning process: the more habitual the association, the greater the obesogenic potential of the food or beverage.  So his diet involves regular doses of “flavorless calories” in the form of bland oils, sugars or proteins.  Alternative strategies include consuming foods with unfamiliar flavors or “crazy spices”, or flavored noncaloric beverages like herb teas. (For more on flavor-calorie association, see my post on Flavor Control Diets).

Some foods and flavors may be naturally appealing to infants and children, but there is strong evidence that food preferences vary considerably among individuals and cultures.  ”One man’s food is another man’s poison”. Roberts describes the interesting story of a Gaku Homma, Japanese cookbook author whose initial impression of Coke was  that it tasted “like medicine” and was repulsed by it. Similarly, Westerners are often repulsed by Asian fermented foods, or delicacies like dog or snake. Certain cultures find insects and grubs to be delectable, but most of us would probably pass, even knowing that such foods represent a nutritious source of calories.  There are many unfamiliar foods, rich in fat, sugar, salt or flavor, that the average fan of potato chips and ice cream would reject, even if hungry. For an interesting discussion of the cultural relativity of food acceptance and rejection of unfamiliar or novel foods, see the article by  John Prescott in the Encyclopedia of Food and Culture.

Likewise, over time we can learn to like flavors and tastes that were once unappealing.  Roberts cites experiments where rats that do not like the taste of saccharine, grow to like it when they are intravenously fed glucose.  There are many “acquired tastes” that we come to like only after repeated exposures.  Our palates are changeable.

If you think that food aromas are naturally or inherently appetizing, rather than relative, ask yourself: Why do we respond to food odors differently than other evocative and pleasant odors – flowers and plants, soil, sea, even pleasant or sensual human scents?  Smelling a rose does not make you hungry. Could we be conditioned to salivate and secrete insulin in response to the smell of a rose if we always sniffed a rose before gulping down a sweet drink? I think so. Pleasant aromas or tastes don’t necessarily generate a drive to eat.  The association between sensation and the drive to eat must be learned.

In fact, both Guyenet and Kessler appear to acknowledge the relativity of taste at certain points in their accounts.  For example, Guyenet notes that taste preferences towards beer or vegetables change as we transition from childhood to adulthood.  It is instructive that Guyenet defines “food reward” in a surprisingly  broad way:

Food reward is the process by which eating specific foods reinforces behaviors that favor the acquisition and consumption of the food in question.  You could also call rewarding food “reinforcing” or “habit-forming”, although not necessarily in an addictive sense.  Food reward is a perfectly normal and healthy part of life, although I believe it can be harmful if it exceeds the bounds of what we’re adapted to.  Food reward is essential for survival in a natural environment, because it teaches you what to eat and how to get it through a trial-and-error process. (Food reward, May 26, 2011)

In this definition of reward, Guyenet seems to move away from the idea that “reward” is an inherent property of food (i.e. fat, sugar, salt) in triggering opioids and dopamine, but rather is a result of conditioning. Sounding very similar to Roberts, Guyenet notes that

Researchers have demonstrated in rodents and humans that pairing a flavor with a source of calories makes us gradually enjoy the flavor more, whether or not it remains paired to calories afterward.  That’s called a “conditioned flavor preference”, and it’s a simple demonstration of food reward in action.  The brain senses the ingested calories and assigns a positive reward value to the cues (flavor, location, etc.) associated with the calories, after which we’ll be more likely to eat something that contains the preferred flavor.

As another example, rats prefer to hang around a place where they have repeatedly received rewarding food.  Have you ever seen a child run after an ice cream truck?  After a certain time, our motivation to obtain a food that we perceive as rewarding increases, and so does our consumption of it.  Rats accustomed to eating human junk food will endure foot shocks and extreme temperatures to obtain it, even when much healthier unprocessed rodent chow is freely available

Put another way:

It doesn’t matter whether or not you like the Little Debbie cake once it’s in your mouth.  It doesn’t matter how you feel afterward.  The only thing that matters is whether or not you’ll buy another one tomorrow.  That’s food reward.

Kessler also acknowledges the role of Pavlovian conditioning in appetite, recognizing that not just flavors, but any cues can serve as reinforcers.  In Chapter 10 of his book, he cites Pavlov’s success in training dogs to salivate in response to the ringing of a bell, even after it is no longer accompanied by food. Kessler discusses Kent Berridge’s related concept of “incentive salience” :

Simply put, incentive salience is the desire, activated by cues, for something that predicts reward.  It’s a learned association — we learn to want a food or some other substance we once liked…Cue-induced wanting, said Berridge is “triggered by the sight of a cookie or someone lighting up a cigarette nearby or clinking the ice cubes in the glass of alcohol…Those kinds of cues have the power to evoke the desire to take that thing again.” Experience imbues the cue with incentive salience. Positive emotions become embedded in cues, which then develop a force of their own. (The End of Overeating, Ch. 10)

So the door has been opened here to the idea that “reward” is not an inherent property of food but rather the consequence of a conditioned association or “pairing” between the calories in the food and a sensible signal or cue.  The cue could be a flavor, but it could just as well be a visual or auditory cue,  a familiar location or a social context.  In this understanding, “reward” not an inherent property of the food, but is rather a learned response to perceptual cues associated with the food.  These cues need only at some point to have become associated with a conditioned expectation of caloric value.

But now we come to the internal contradiction in the Kessler-Guyenet theory of food reward:  Is “reward” objective and invariant — or relative, subjective and variable?  It cannot be both. To say that reward is “relative” means that it varies markedly among individuals and across cultures, but that does not make it any less real.  It can be a powerfully motivating force, driving the obese to overeat and even binge to unhealthful extremes.  But to acknowledge the subjectivity and relativity of food reward is at odds with the idea that there is such thing as inherently “hyperpalatable” food that is irresistibly obesogenic in and of itself.

An alternative explanation: impaired metabolism.  I’m not denying here that people crave or get addicted to foods like potato chips, cookies and ice cream.  No doubt these people find the flavors salient and compelling, even to the point of addiction. But it’s not the flavor that causes the behavior in the first place. The flavor only becomes a strong cue under certain conditions.  That’s obvious from the simple fact that many people, eating the very same foods, do not find them to be addictive.  While I occasionally enjoy a cookie or some ice cream, I actually find it repulsive to eat more than a modest amount.  While I used to like soda, I now experience Coke as sickly sweet.  And I think I’m not alone in that reaction.

A more likely explanation is that food addicts have altered, perhaps even damaged, their metabolisms.   They are most likely insulin-resistant and leptin-resistant as a result of many possible factors, including obesity, stress and inflammation of their insulin receptors and glucose transporters.   Guyenet aptly describes how inflammation and lipotoxicity damage the hypothalamus:

There’s an additional factor that I’ve come to believe may be an “elephant in the room” when it comes to insulin/leptin resistance and chronic inflammation, and that is, ironically, energy excess.  Glucose and fatty acids, the body’s main two fuels, are toxic when present in the bloodstream in excess.  When someone eats too many calories, his body has to deal with the excess.  The healthiest way of doing this is actually to shunt the excess energy into fat tissue where it is inert.  If the fat tissue does not have a sufficient affinity for the excess fat, free fatty acid levels in the circulation may rise, and tissues and cells may accumulate fat and fat metabolites…if fat mass increases enough, fat cells become insulin resistant, release more fatty acids into the circulation and fail to clear fatty acids from the circulation after a mixed meal.  Essentially, fat tissue loses its formerly high affinity for excess fat, and these undesirable fat metabolites accumulate in lean tissues in a manner reminiscent of lipodystrophy.  This contributes to insulin resistance and glucose intolerance by the same mechanism described above, creating an excess of circulating glucose as well, which together with the excess of fatty acids can enhance chronic inflammation, further insulin resistance and damage the insulin-secreting pancreas.

…Therefore, it’s possible that an excess of circulating fatty acids (and perhaps glucose) itself acts to raise the setpoint through the gradual accumulation of fatty acid metabolites and inflammation in the hypothalamus, promoting leptin resistance and creating a “cascading failure” of energy balance regulation, glucose metabolism and inflammatory signaling.  This would explain why people in affluent societies have trouble staying lean as they age, as well as why obesity is so difficult to treat.  I think this is likely to be a late stage process, occurring after significant body fat accumulation and essentially “cementing” the increase in body fatness.  The early stage that causes the initial rise in body fatness probably has more to do with food reward/palatability/availability, although that should remain a factor even after obesity is well established…The basic idea is that in genetically susceptible people, excessive food reward/palatability/availability and inactivity cause overconsumption and an increase in the body fat setpoint, followed by the eventual accumulation of fat metabolites and inflammation in the hypothalamus, which exacerbate the problem and make it more difficult to treat.  Other factors, such as micronutrients, gut flora, fiber, fat quality, polyphenols, sleep and stress, may also play a role.  I think this is a reasonable working hypothesis of why obesity has increased so rapidly in the last 30 years, and is so difficult to treat once established.  I believe these ideas are broadly consistent with the research and opinions of senior obesity researchers I respect. (Roadmap to Obesity, August 25, 2011)

Cause and effect. Where I believe Guyenet goes wrong in the above passage is in postulating that “the early stage” of obesity is driven by primarily by food reward causing overconsumption, which then leads to obesity and leptin resistance.  I think the cause and effect relationship is reversed. Certainly “normal” reward is part of a healthy appetite, but that doesn’t lead to obesity.  It is the leptin resistance of obesity that sets one up for food reward to become pathogenic.   According to Robert Lustig, the normal satiating effect of insulin within the brain (CNS) becomes impaired in those with insulin and leptin resistance:

Although CNS insulin levels tend to reflect serum insulin levels, the relationship breaks down in obesity states. In obesity, there is proportionally less CNS insulin; the expression of the CNS insulin transporter is decreased in several obesity models. This paucity of insulin available for satiety signaling may represent a form of CNS insulin resistance. (Lustig, Fast Food, Central Nervous System Insulin Resistance, and Obesity)

Put simply, it takes more time and larger quantities food or beverage for insulin-resistant individuals to become sated, because the appetite-suppressing or “shut off” effect of insulin in the hypothalamus is impaired.  Added to this is the fact that obese, insulin-resistant individuals typically have a grossly amplified preprandial insulin response, which means that blood glucose is more easily stoked by mere appetite cues like the sight, aroma, or even thought of food.  Frequent, regular and familiar eating of these reward foods further strengthens the reinforcement.  Even stress can trigger this hunger cycle.  This leads to a very strong drive to start eating and great difficulty in shutting off the eating.  And with more overconsumption of food and the resultant obesity, a vicious cycle sets in, leading to heightened insulin-resistance and leptin-resistance.  Once this vicious cycle begins, the psychological component of food cravings and addictions is enhanced.  The association between flavor cues — or any cues — and consumption of the food is strengthened.  And the food becomes more and more palatable, even “hyperpalatable”.  But it is the impaired metabolism of obesity and the reinforcing eating patterns that make these foods hyperpalatable to the individual, not the other way around.

Foods are not inherently hyper-rewarding.  Rather, an impaired metabolism, combined with reinforcing eating patterns  lead to food becoming hyper-rewarding. 

I can anticipate the following objection to my argument:  Am I saying that any food can become hyperpalatable or addictive?  If so, why are foods like french fries, bread, cookies, chocolate and ice cream craved more than celery, cucumbers and lamb chops?   The answer, I think, is that if you are leptin-resistant and insulin-resistant, these high calorie foods provide a sufficiently rapid “bolus” injection of calories into the bloodstream to overcome any initial preprandial drop in blood glucose, and to spike insulin sufficiently high to overcome the CNS insulin resistance and thus satisfy appetite.  However–and this is a key point–not everyone finds junk foods to be irresistable.  Most insulin sensitive individuals are readily sated on pizza or dessert.  And not everyone even finds these foods to be enjoyable.

Another important factor in the addictiveness of food is the reduction or impairment in dopamine receptors in the brains of the obese, as documented by PET scans. Interestingly, a similar reduction in dopamine receptors is seen in drug addicts and depressed individuals.  This could be a result of the overstimulation by raised levels of dopamine from the “bolus” of large meals or binges. resulting in a homeostatic downregulation of receptors.  I’ve discussed this in more detail in my post Change your receptors, change your set point. Probably any large amount of calories, even with unfamiliar, less palatable, or weaker flavors would do the same trick.  For a short time, there would be frustration due to reduced dopamine signaling  — until the brain learned the new flavor-calorie association.

Bland food diet.   From his theory of food reward, Guyenet proposes a way out:  Eat bland foods.  He supports this by citing evidence that pre-industrial cultures such as the Kitavans eat a diet that is quite bland, despite being high in carbohydrates, and thereby they remain lean and healthy.  He references studies on the effects of bland food diets in lean and obese humans (by Hashim and Van Italie, and by Michael Cabanac) to support his thesis.

Investigators have known for decades that the cafeteria diet is a highly effective way of producing obesity in rodents, but what was interesting about this particular study from my perspective is that it compared the cafeteria diet to three other commonly used rodent diets: 1) standard, unpurified chow; 2) a purified/refined high-fat diet; 3) a purified/refined low-fat diet designed as a comparator for the high-fat diet. All three of these diets were given as homogeneous pellets, and the textures range from hard and fibrous (chow) to soft and oily like cookie dough (high-fat). The low-fat diet contains a lot of sugar, the high-fat diet contains a modest amount of sugar, and the chow diet contains virtually none. The particular high-fat diet in this paper  (45% fat, which is high for a rat) is commonly used to produce obesity in rats, although it’s not always very effective. The 60% fat version is more effective.

Consistent with previous findings, rats on every diet consumed the same number of calories over time… except the cafeteria diet-fed rats, which ate 30% more than any of the other groups. Rats on every diet gained fat compared to the unpurified chow group, but the cafeteria diet group gained much more than any of the others. There was no difference in fat gain between the purified high-fat and low-fat diets.

So in this paper, they compared two refined diets with vastly different carb:fat ratios and different sugar contents, and yet neither equaled the cafeteria diet in its ability to increase food intake and cause fat gain. The fat, starch and sugar content of the cafeteria diet was not able to fully explain its effect on fat gain. However, each diets’ ability to cause fat gain correlated with its respective food reward qualities. Refined diets high in fat or sugar caused fat gain in rats relative to unpurified chow, but were surpassed by a diet containing a combination of fat, sugar, starch, salt, free glutamate (umami), interesting textures and pleasant and invariant aromas.

Guyenet’s interpretation is that the rats ate more of the “cafeteria diet” because it was more palatable, presumably due to the higher fat, starch and sugar content, than the equally calorie dense blander diets. But this is not proven.  How do we know it was more “palatable”, if this is a subjective quality?  All we know is that more of the cafeteria diet was consumed.  We can of course define that as palatability, but that would make the argument circular.  The real question is:  Do we eat more calories because inherent “palatability” or taste characteristics?  Or do foods become  perceived as more palatable because of prior food experience, eating patterns and associations that modify neural circuitry and the drive to eat?  Palatability appears not to be something inherent in food, but rather something changeable. We do not know what diets or reinforcement schedules the rats were raised on before Cabanac’s conducted his experiments.

From these and other observations, Guyenet concludes:

Some people may be inclined to think “well, if food tastes bad, you eat less of it; so what!” Although that may be true to some extent, I don’t think it can explain the fact that bland diets affect the calorie intake of lean and obese people differently. To me, that implies that highly rewarding food increases the body fat setpoint in susceptible people, and that food with few rewarding properties allows them to return to a lean state. (Food Reward, A Dominant Factor in Obesity, Part II)

In recognizing that bland diets have different effects on the lean and the obese, Guyenet here seems to made a full retreat from asserting the explanatory power of food reward as a primary driver. The relativity of taste here reveals that it must be a consequence, not a determinant, of metabolism and neural conditioning.

What can we do?  If you believe that tasty food is inherently addictive, it is reasonable to seek out bland food, and avoid strong flavors, fat, sugar and salt.  But is this necessary?  Do we have to give up not just “junk foods” like Big Macs, french fries and ice cream — but also more healthful foods that are flavorful, fatty, sweet or salty? What about lamb curry (fatty and flavored), berries and cream (sweet and fatty) or salted steak?  I think not. Flavor, fat, salt and even a modest amount of sugar is not the seed of obesity.  Rather, it is the effect that foods have on our hormones and receptors that we should think about.  To avoid obesity, we should strive to maximize our insulin sensitivity and leptin sensitivity. This can be done by a variety of measures, discussed elsewhere on this blog, including:

• weight loss, particularly abdominal fat
• intermittent fasting
• avoiding inflammatory foods and toxins that impair receptor sensitivity
• supplementing with fish oil, magnesium and vitamin D for receptor health
• avoiding chronic stress, but pursuing intermittent, intense “good” stress, such as:
• > high intensity exercise
• > cold showers
• > brief thrills and unpleasant challenges

…

Bon apetit.

Why is it so hard to make permanent changes to your habits, your health, and your happiness?  Some of the most difficult struggles in life involve losing weight (and keeping it off), overcoming addictions, and recovering from depression. Many diets and therapies deliver great short term results, but the most common pattern appears to be relapse.  It often seems that you are destined to fulfill some biological program — that you are stuck with a high body weight set point or an addictive or depressive personality that cannot be escaped in the long run.

This pessimistic message is prevalent among those who have investigated the track records of the “helping” industries: the weight loss companies, the addiction recovery centers, and the various schools of psychology and psychiatry. Unlike the advocates, those who investigate them often find the results are less than what the practitioners might want you to believe.  In the arena of dieting and weight loss, books such as “The Dieter’s Dilemma” (Bennett and Gurin, 1982), and  ”Rethinking Thin”  (Kolata, 2008) echo the original set point theory first propounded by Gordon C. Kennedy in the 1950s; they conclude that your body weight is largely predetermined by a biological set point that is handed to you at birth, plus or minus about ten pounds. I do agree that sustained weight loss cannot be achieved through sheer will power alone, or simply by using diet and exercise in order to create a calorie deficit. Yet, while there is some plausibility to the set point theory, I am convinced that it is wrong because it overlooks some important factors. I’ve already given some of my reasons for my disagreement with set point theory in other posts on this blog (Flavor control diets, How to break through a plateau). But in this post I’ll present some strong evidence for an alternative theory, based on the homeostatic regulation of cellular receptors for hormones and neurotransmitters. This is a variable set point theory which I call the receptor control theory. This theory proposes a mechanism that controls appetite and body weight, as well as regulating the balance of  energy and pleasure in your life. It provides practical tools to lose weight and keep it off, overcome addictions without relapse, and move out of depression into happiness.

But first, let’s consider some common approaches for dealing with three different  health issues:

1. Obesity/Diabetes. To lose weight, reducing diets are employed that create an energy deficit.  The most effective of these diets work by actively modulating the levels hormones such as insulin or leptin, by modifying the type of food we eat (low glycemic or low carbohydrate are best), or the size and timing of meals.  In the case of advanced diabetes (an insulin deficiency), exogenous insulin is administered periodically in a controlled manner. Alternately, diet pills or other appetite suppressants are used to moderate certain hormones and peptides involved in satiety.  The back-up strategy is to learn how to cope with always being somewhat hungry.
2. Addiction. Addictive cravings from cocaine, alcohol, or other substances or activities have been associated with overstimulated dopamine “reward” circuits.  Some  treatments involve the use of antidepressants to elevate baseline dopamine levels, The back-up strategy is to counsel abstinence to avoid triggering the dopamine circuits in the first place.
3. Depression. To counteract depression, antidepressant drugs (typically SSRIs) are prescribed to boost levels of neurotransmitters such as serotonin or dopamine. Or, we may try non-drug supplements or dietary options to increase the level of these neurotransmitters: for example, serotonin precursors such 5-HTP,  tryptophan-rich food such as turkey and carbohydrates such as potatoes, which allow dietary tryptophan to readily produce serotonin in the brain. The back-up strategy is psychotherapy to provide insight or coping skills to better deal with the underlying depression.

The organic imbalance model. These three seemingly different treatments share a common thread: they are all based on conceiving health problems as intrinsic organic imbalances in our metabolism or neurochemistry that you are either born with or develop early in life, and over which you have little control.   Once you accept this model, there are two basic strategies: an “active” strategy to rebalance internal biochemistry, usually by means of drugs, supplements, or diet. And a “passive” back-up strategy of accepting that you are biochemically different, and counseling ways to cope with these organic conditions as best youe can, while trying to minimize the risk of triggering flare-ups due to relapse, bingeing, or depressive episodes.

Signaling compounds. I’ll focus here more on the “active” interventions which involve trying to directly rebalance the levels of “biochemical messengers” or signaling compounds circulating in our bodies. I’m referring to hormones like insulin and leptin, glucagon, or adrenaline; or neurotransmitters like serotonin or dopamine, which are produced in response to external stimuli.  According to the imbalance model, the levels of these signaling compounds are out of balance: there is a surplus or deficiency of “communication” that needs to be adjusted. The resulting “message” conveyed by the signaling compound is “too loud” or “too soft” for normal bodily function.  So to correct this, a therapeutic intervention is devised which attempts to restore our health by adjusting the amount of the signalling compound in our system.  In effect, the treatment attempts to turn up or turn down the “volume” of the message by adjusting the amount of signaling compound, in order to re-normalize our response to external stimuli.

These active medical or dietary interventions should work, if the imbalance model is correct.  But in many cases the treatments backfire:  after perhaps seeing a short term benefit the effect dissipates, and in some cases symptoms actually worsen, or side effects develop.  After some initial weight loss, the weight is regained.  Attempts to overcome addiction frequently end with relapse and failure. And depression returns. The problem is that we are not mechanical machines, we’re adaptive organisms, regulated by homeostasis. Trying to control message intensity may work for a short time, but the body outsmarts us and compensates for the intervention. Our wonderful, adaptive bodies react to the increased level of signaling compounds by becoming less responsive to them, just as we learn to tune out a dog that constantly barks for attention.  When the message volume is turned up, the receiver volume is turned down.

Our efforts to change seem to be hampered by biological programs that resist these efforts at biochemical rebalancing. Some will explain this by arguing that’s because we are born with a biological set point that our body will “defend” or an addictive or depressive personality that we can’t shake.  Try as we might to fight this in the short term, it’s almost impossible to succeed in the long run.  A lucky few may prevail, but the vast majority are doomed to their biology destiny.

Even if you manage to normalize the level of signaling compounds, you are now stuck with another problem:  you are dependent on some drug, supplement, or special dietary restriction for the long term — maybe even for the rest of your life. Drug companies and dietary supplement suppliers are happy to provide you with a lifetime supply of these compounds for a price.  I don’t know about you, but I’d rather not be dependent long term on drugs or supplements, or even restrictive diets, if it doesn’t have to be that way.

There are grounds for pessimism here.  But there may be a better solution that gives us back control of our fate:  Receptor regulation.

Receptor regulation. Receptors are “message receivers” located throughout our bodies. They are typically transmembrane proteins located on the surfaces of cells, and they bind with hormones and neurotransmitters to “receive” the signal and initiate a sequence of changes in our bodies — often profound system-wide changes in energy utilization, tissue growth, or the perception of pleasure and pain. For some reason, receptors don’t get the public attention that gets showered on the communication chemicals — the hormones and neurotransmitters.  And yet, as I shall argue, the receptors may be far more important than the signaling compounds that they interact with, because they do not change by the minute or hour, but are long-lasting parts of the control systems of our bodies.  If hormones and neurotransmitters are the “software”, receptors are the “hardware”.

The key process to understand is called receptor regulation, the process which controls the number, location and sensitivity of receptors. There are two forms: upregulation (an increase in the number and/or sensitivity of receptors in each cell) and downregulation (the reverse process). Wikipedia explains downregulation by describing how insulin resistance develops in response to elevated insulin levels:

The process of downregulation occurs when there are elevated levels of the hormone insulin in the blood. When insulin binds to its receptors on the surface of a cell, the hormone receptor complex undergoes endocytosis and is subsequently attacked by intracellular lysosomal enzymes. The internalization of the insulin molecules provides a pathway for degradation of the hormone as well as for regulation of the number of sites that are available for binding on the cell’s surface without doubts. At high plasma concentrations, the number of surface receptors for insulin is gradually reduced by the accelerated rate of receptor internalization and degradation brought about by increased hormonal binding. The rate of synthesis of new receptors within the endoplasmic reticulum and their insertion in the plasma membrane do not keep pace with their rate of destruction. Over time, this self-induced loss of target cell receptors for insulin reduces the target cell’s sensitivity to the elevated hormone concentration. The process of decreasing the number of receptor sites is virtually the same for all hormones; it varies only in the receptor hormone complex. (Italics added by me for emphasis).

So not only are the insulin receptors drawn inside the cell (like a turtle into its shell); they are also actively digested and degraded, making them less available to readily redeploy when glucose and insulin levels drop again.  New receptors are always being synthesized, but they are degraded more quickly than they can be replenished if insulin levels remain high. The resulting downregulation of insulin receptors forms the basis for the condition of insulin resistance, in which insulin at normal levels loses its ability to efficiently shuttle glucose from the bloodstream into liver, muscle, brain, adipose or other tissues; the body responds by further increasing insulin, resulting in a vicious cycle of hyperinsulinemia. Reversing this process — growing new insulin receptors — takes time and requires sustained periods with low circulating levels of insulin in order to foster the growth of new receptors.

It is quite revealing to look at how how receptor regulation can undermine “message control” treatments,  due to the way the body adapts. Let’s take a look again at how this plays out in the above three examples of obesity, addiction, and depression:

1.  Obesity. Obesity is associated with high levels of two hormones: insulin and leptin. Normally, an increase in the level of either of these two hormones induces satiety upon reaching the hypothalamus in the brain. Leptin levels in the body increase with the amount of body fat, so leptin has been proposed as a physiological correlate for our “set point” weight: when body fat falls below a certain level, appetite induces us to eat more; when body fat increases, the associated rise in leptin levels leads to satiety. Insulin plays a similar but different role; it tends to regulate appetite on a shorter timescale than leptin, varying during each meal, and is more closely associated with visceral fat of the type more commonly found in men, whereas appetite regulation by leptin operates on more of a daily timescale and responds more closely to subcutaneous fat of the type more common in women. Insulin, of course, is directly involved with the storage and release of metabolic fuels. There are also many other regulatory hormones and sensory peptides, such as ghrelin, CCK and PYY, which adjust appetite based upon meal timing, gut sensations, and other inputs.  But insulin and leptin are key drivers of appetite.

The discovery of leptin, the “satiety hormone” by Jeff Friedman at Rockefeller University in 1993 provoked great excitement and expectations.  A well written account of this discovery is detailed in “Rethinking Thin“, the above-mentioned book by Gina Kolata. Studies in leptin-deficient ob mice and humans showed that individuals with defective production of leptin became ravenous and obese.  So the logical conclusion was leptin itself may be the magical “set point” compound that determines our weight.  Therefore, we should be able to provide leptin to the overweight to help them shed pounds. And in fact, adminstering leptin does work to counteract obesity in mice and humans that are genetically incapable of producing normal leptin, as Kolata describes poignantly in her chapter “The Girl Who Had No Leptin”.  It even works initially in normal or lean mice to reduce body fat. Amgen acquired the rights to leptin from Rockefeller University for $20 million plus royalties in anticipation of imminent commercialization. But after a long-term study in humans, the October 1999 issue of  JAMA reported disappointing results indicating very little weight loss, and even that in only in a small percentage of subjects. As Kolata observes:

The question, though, was, Why didn’t the obese people in Amgen’s study respond to leptin? The possibiity, or perhaps the likelihood, was that leptin was not their problem. These people were making plenty of leptin–they were not the human equivalent of the ob mice. And since adding more leptin did not make them lose weight, it must be that the hormone was being blocked from acting somewhere along its passage from the fat cells to the appetite-controlling pathways in the brain…Then [scientists] discovered that leptin can do something else. It can actually change the brain’s wiring diagram, strengthening circuits that inhibit eating and weakening the ones that spur the appetite. It can exert this effect at a critical period early in life, perhaps influencing appetite and obesity in adults.  And, in adulthood, leptin can again alter the brain’s wiring, permanently changing an animal’s appetite and weight. (RT, pp. 163-165).

The problem is often that excessive sustained levels of leptin, common in the overweight or obese,  can cause “leptin resistance” in which the leptin receptors are downregulated, so that they are fewer in number and become less sensitive to the leptin signal. As Byron Richards indicates in The Leptin Diet:

In overweight people, the communications involving insulin and leptin are inefficient. It is like making a phone call where no one answers. Insulin resistance and leptin resistance mean that the hormones don’t communicate efficiently in response to food. Thus a person has to overeat in order to get enough leptin into the brain to get a full signal. The pancreas may not hear the leptin signal to stop making insulin, which leads to excess insulin, fatigue, and possibly even more hunger within a few hours of eating…Several hours following the meal the extra insulin ends up taking too much sugar out of the blood, making a person hungry and tired-headed. (TLD, p 36)

With leptin resistance, adding more leptin no longer effectively inhibits appetite, because the brain and body have a reduced ability to respond to the extra leptin.  Conversely, lean individuals typically have more leptin receptors and greater leptin sensitivity, so their appetite is satisfied even at reduced leptin levels.  In short, the leptin system adapts so that the number of leptin receptors adjusts to the amount of leptin.

Interestingly, obesity is also associated with reduced number of receptors for dopamine, a neurotransmitter associated with pleasure or reward circuits in the brain. In 2001, Gene Jack Wang and Nora Volkow of the U.S. Department of Energy’s Brookhaven National Laboratory used Positron Emission Tomography (PET) brain scans to look at dopamine receptors in the brains of obese and normal individuals:

Obese individuals, the scientists found, had fewer dopamine receptors than normal-weight subjects. And within this obese group, the number of dopamine receptors decreased as the subjects’ body mass index, an indicator of obesity, increased.  That is, the more obese the individual, the lower the number of receptors.

A 2008 study of women and adolescent girls in New Zealand showed that this receptor deficit is at least partly genetic. The overweight females had the Taq1A1 gene that is associated with fewer dopamine receptors. This receptor deficit in the obese led them to overeat to achieve the level of pleasure or satiety that normal individuals reached with less food. This reduced level of dopamine receptors tends to make life a bit less pleasant for the obese when they are hungry and without food. Ingestion of food, particularly carbohydrates, temporarily raises the level of dopamine, eliminating the “pleasure deficit” and rewarding eating behavior.  Excessive eating or bingeing raises the dopamine levels even higher than normal, which can lead to a further downregulation of dopamine receptors, only worsening the craving problem. This effect is not only influenced by genes, but by diet; a 2010 study of rats fed a supermarket “junk food” diet showed raid desensitization of dopamine receptors a significant increase in appetite, and an unwillingness to return to eating “healthy” food.

The connection between obesity and the number and sensitivity of dopamine receptors is perhaps not so surprising, given how highly rewarding food can be for the obese; for many of the overweight, food becomes an addiction.  It is still quite striking that this translates to such a significant decline in the number of dopamine receptors, while the baseline level of dopamine actually increases.  Here, as with insulin and leptin, we have yet another example of reduced receptor levels being associated with obesity.  By analogy with insulin resistance and leptin resistance, we might say that the strong appetite of the obese is a direct result of “dopamine resistance”.

2. Addiction. What is particularly interesting is that these low levels of dopamine receptors are also characteristic of drug addicts and alcoholics.  Nora Volkow, one of the directors of the Brookhaven study, subsequently became director of NIDA, the National Institute of Drug Abuse. part of NIH, but her research on addiction actually predates the study she did on brain activity in the obese. She used PET brain scans to study dopamine receptors levels in alcoholics, cocaine addicts, and addicted smokers.  And, as you might guess, the same pattern of reduced levels of dopamine receptors was observed in addicts vs. non-addicted controls.  This is illustrated in the PET scan to the right, which shows dopamine binding activity for addicts (top row) vs. non-addicts (bottom row). Regions of greatest dopamine receptor activity are indicated with a color scale starting from red (most active), descending through yellow and green to blue and purple (least active).

The mechanism downregulation of dopamine receptors by cocaine has been elucidated:

Cocaine binds tightly at the dopamine transporter forming a complex that blocks the transporter’s function. The dopamine transporter can no longer perform its reuptake function, and thus dopamine accumulates in the synaptic cleft. This results in an enhanced and prolonged postsynaptic effect of dopaminergic signaling at dopamine receptors on the receiving neuron. Prolonged exposure to cocaine, as occurs with habitual use, leads to homeostatic dysregulation of normal (i.e. without cocaine) dopaminergic signaling via down-regulation of dopamine receptors and enhanced signal transduction. The decreased dopaminergic signaling after chronic cocaine use may contribute to depressive mood disorders and sensitize this important brain reward circuit to the reinforcing effects of cocaine (e.g. enhanced dopaminergic signalling only when cocaine is self-administered). This sensitization contributes to the intractable nature of addiction and relapse.

3.  Depression. A reduced number or sensitivity of neurotransmitter receptors has also been linked to mood disorders such as major depression. Depression has been associated with shortages of at least two neurotransmitters:  dopamine (which is associated with drive, motivation and pleasure), and serotinin (which is associated with a sense of well-being and pleasure).  While dopamine receptors are located largely in the brain, a little known fact is that only about 20% of serotonin receptors are in the brain, most of the other 80% are in the gut, blood platelets, and other organs.  That might help explain why serotonin is also associated with food and satiety.   Different types or depression are often associated with a different imbalance of neurotransmitters, so despite the prevalence of SSRIs, which are intended to restore serotonin levels, some forms of depression respond better to antidepressants which boost dopamine levels.

While antidepressants work for many people, a surprising number — some estimates put it at 50% or higher — are unresponsive. Furthermore, long term use of SSRI’s can have the effect of downregulating serotonin (5-HT2A) receptors with adverse results:

Another adaptive process provoked by SSRIs is the downregulation of postsynaptic serotonin 5-HT2A receptors. After the use of an SSRI, since there is more serotonin available, the response is to decrease the number of postsynaptic receptors over time and in the long run, this modifies the serotonin/receptor ratio. This downregulation of 5-HT2A occurs when the antidepressant effects of SSRIs become apparent. Also, deceased suicidal and otherwise depressed patients have had more [presynaptic] 5-HT2A receptors than normal patients. These considerations suggest that 5-HT2A overactivity is involved in the pathogenesis of depression

The last sentence in the above quote again points to the fact that a deficiency of post-synaptic serotonin receptors, in combination with  an excess of serotonin from diet, antidepressants, or elsewhere,  may play a role in both the genesis and worsening of depression.  The same phenomenon of receptor downregulation together with excess neurotransmitter has been noted with other antidepressants, such as MAO inhibitors and buproprion, that stimulate the production or prolong the lifetime of dopamine in the synapse.  This can lead to tolerance and withdrawal effects.

In short, in all these cases — obesity, addiction, and depression — receptors are becoming less sensitive to a signaling compound as a reaction to excessive levels of that compound.  So too much insulin and leptin lead to insulin and leptin resistance, too much dopamine to a downregulation of dopamine receptors.

………………………………….

HOW TO UPREGULATE YOUR RECEPTORS. So if directly changing the amount of signaling compounds is frequently frustrated by receptor downregulation, is there anything you can do to upregulate the receptors?  Fortunately, the answer is yes.  There are a number of measures that have proven particularly effective for deliberately increasing the number and sensitivity of key classes of receptors:

Step 1:  Strenuous exercise. Regular, intense exercise can upregulate your insulin receptors. In Dr. Bernstein’s Diet Solution, Richard Bernstein explains the role of exercise in actually reversing insulin resistance by growing new muscle tissue, and by increasing the density of glucose transporter receptors in muscle and other tissues.  While his advice is directed primarily towards diabetics, it applies more broadly to anyone with some degree of insulin resistance That includes most of us.  According to Dr. Bernstein:

The higher your ratio of abdominal fat to muscle mass, the more insulin-resistant you’re likely to be. As you increase your muscle mass, your insulin needs will be reduced…Long-term, regular strenuous exercise also reduces insulin resistance independently of its effect upon muscle mass…In my experience, it takes about two weeks of daily strenuous exercise to bring about a steady, increased level of insulin sensitivity…via increased production of glucose transporters in muscle cells. (DBDS, p. 170-1).

Furthermore, the exercise must be strenuous and “anaerobic” – not aerobic.  There are two reasons for this:

First, the blood sugar drop during and after continuous anaerobic exercise will be much greater than after a similar period of aerobic exercise. Second, to accomplish efficient transport of glucose into muscle cells, as muscle strength and bulk develop, glucose transporters in these cells will greatly increase in number. Glucose transporters also become more numerous in tissues other than muscle, including the liver.  (DBDS, p. 180)

Glucose transporter (GLUT4) receptors are upregulated by intense exercise.  A study reported in the New England Journal of Medicine showed that this upregulation begins to happen within hours, but significant and sustained improvement requires repeated exercise sessions over several weeks.  When insulin levels are kept low, the glucose transporters migrate from a location inside the cell to protrude beyond the cell surface, becoming more available to bind glucose and shepherd it into the interior of the cell.  With time, the cells can actally express or “grow” additional receptors, increasing the overall rate of glucose transport.  This increased response rate is synonymous with “insulin sensitivity”.

The benefits of anerobic exercise extend not only to upgregulation of insulin receptors, but also to maintaining high levels of dopamine “reward” receptors. A study of exercised rates by McRae et al at University of Texas showed that regular exercise has a protective effect on D2 dopamine receptors, while keeping levels of dopamine (DA) and dopamine metabolite (DOPAC) low.  Unexercised rats saw both a decrease in D2 receptor density and an increase in circulating dopamine.

Step 2:  Calorie restriction and intermittent fasting. Another brain scan study at Brookhaven National Laboratory showed that restricted eating led to higher numbers of dopamine receptors in obese rats:

The scientists found that genetically obese rats had lower levels of dopamine D2 receptors than lean rats. They also demonstrated that restricting food intake can significantly increase the number of D2 receptors, partially attenuating a normal decline associated with aging.

This research corroborates brain-imaging studies conducted at Brookhaven that found decreased levels of dopamine D2 receptors in obese people compared with normal-weight people,” said Brookhaven neuroscientist Panayotis (Peter) Thanos, lead author of the current study, which will be published online in the journal Synapse on Thursday, October 25, 2007.

One of the essential points to understand here is that if calorie restriction and intermittent fasting are effective, it is not for the reason that most people think explains this (that you are creating a calorie deficit).  Rather, intense exercise and fasting work because they resensitize and grow your insulin and dopamine receptors in a way that allows you to get enough energy and pleasure from eating less food.   This means that not only are the receptors upregulated, but you also get the energy and pleasure when you need it.  So restricting calories is not good enough.  You must eat foods that maximize insulin senstivity (e.g. containing adequate essential fatty acids, protein, magnesium, etc.) and foods which give you enough pleasure so as to satisfy your “pleasure budget”, but not so much as to downregulate your dopamine receptors.  My experience is that intermittent fasting, using a varied diet, is the best way to do this.  One reason that pure “starvation diets” like that used in the Minnesota Starvation Experiment may have failed is that the diet failed to supply adequate nutrients that to support receptor function for cellular energy and pleasure.  (The 1560 calorie/day regimen consisted only of potatoes,  rutabagas,  turnips,  bread and macaroni — so go figure!)

A particularly effective protocol for improving insulin sensitivity and upregulating glucose transporter receptors is called “fasted workouts”: a combination of intense exercise and intermittent fasting, in which eating is postponed until after one works out.  One of the foremost practioners of this approach is Martin Berkhan, who I’ve referenced on the Fitness page of this blog, and whose Leangains blog I’ve listed under the Diet links.  Martin summarizes the research by DeBock et al. and Cluberton et al. that documents the physiological beneifts of fasted workouts, including enhanced insulin sensitivity based upon a six-week study with four 60-90 minute workouts per week. The study controlled for dietary intake, and compared results of those who fasted (F) with the control group (C) that ate prior to working out. Among other variables, the study compared changes in the levels of the GLUT4 transporter, a type of insulin receptor in the muscles, between the F and C groups:

Glucose transporter type 4 is a protein responsible for insulin-regulated glucose transport into the muscle cell. It increased by a whopping 28% in F but only 2-3% in C (not mentioned in the paper but this is my estimate based on the graphs). This partly explains why F saw superior results in regards to glucose tolerance and insulin sensitivity. Since GLUT4 is triggered by AMPK, which is increased when glucose availability is low, i.e. during fasted training, one would assume the GLUT4 increase could then be explained by an increase in AMPK. This was found to be true: AMPK increased by 25% in F, which correlated closely with the increase in GLUT4 content.

Step 3: Deconditioning and extinction. Pleasure reward circuits do not change overnight.  But the good news is that there is plenty of evidence that these reward circuits can be extinguished by classical conditioning techniques.  I’ve discussed these deconditioning techniques in depth on the Psychology and Diet pages of this blog, and I’d recommend looking there for details.  Extinction involves merely refraining from the undesired behavior (eating, addictive drugs) and allowing the cravings to happen without reinforcing them.  It may surprise you how quickly your reward circuits recover, and it is very likely that this involves upregulation of dopamine receptors, so that the brain is more easily “satisifed” without the previously craved behavior. Deconditioning is more active than extinction; it requires actively exposing yourself to cues which normally set off the addictive response.  This may sound extremely difficult, but is attested to by extensive research, as well as the personal experience of several people who have posted here on the Forum, including myself.   One of the more successful appliations of active deconditioning is the Sinclair Method, which has been used successfully to extinguish alcoholism while training the former alcoholic to drink moderately. The key is the use of a dopamine blocker, naltrexone, to block the reward circuits during exposure.

Any type of extinction should benefit from simultaneous reinforcement of healthy alternative sources of pleasure, while engaging in exercise and intermittent fasting to rebuild the density and sensitivity of receptors.  Unless you increase your level of dopamine receptors, you’ll always be vulnerable to the temptation of any pleasure that can “fill your pleasure deficit”.

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THE RECEPTOR CONTROL THEORY. Based upon a synthesis of extensive evidence, I’m putting forward in this post an alternative to the classic set point theory of Gordon Kennedy:  the receptor control theory.  This is a general hypothesis of biological regulation which applies to more than just weight control; it applies to any homeostatic variable that is controlled by cellular receptors — even, for example, pleasure and motivation. Whereas the classic set point theory of body weight posits a fixed genetic set point for each individual,

the receptor control theory postulates that our set points for regulating weight, energy, or pleasure are variable; they are directly related to the number, sensitivity and location of cellular receptors in our bodies, and can be modified by changing the number and sensitivity of these receptors.

For example, the set point for your body fat is controlled by insulin and leptin sensitivity, which is determined by the number and functional sensitivity of insulin and leptin receptors throughout your body.  As the number and sensitivity of insulin and leptin receptors decreases, body weight set point goes up. But unlike the set point theory, body fat set point can also go down by increasing the number and sensitivity of these receptors — for example by the use of strenuous exercise, intermittent fasting, and extinction.

If you don’t change the number and sensitivity of your receptors, your set point will not change.  Under these circumstances, the receptor control theory agrees with the classic fixed set point theory. However, the receptor control theory provides a way to change your set point by upregulating your receptors.

The pleasure budget. The receptor control theory goes beyond weight management to explain more generally the regulation of pleasure in your life.  If you have ample dopamine receptors, then a wide variety of stimuli– including food, social interactions, work, and other interests– should provide you with sufficient pleasure to make life not just bearable, but interesting.  However, if you end up with an undersupply of dopamine receptors — whether it be from birth, addictions or unremitting stress — then your baseline pleasure “set point” will be low and you’ll be vulnerable to depression, low self-esteem and other aspects of unhappiness. Addictive escapes may provide temporary (but unsustainable) bursts of dopamine, serotonin, and other feel-good neurotransmitters, but at the cost of further downregulating dopamine receptors and feeling worse later on.

It may be the case that all of us have a certain “pleasure budget” — perhaps we need a certain amount of pleasure every week, and we’ll find a way to get it, one way or another.  One of the commenters (zdd) to my earlier post on The opponent-process theory of emotion expressed this point well, when speculating about why diets like Shangri-La and Atkins work so well initially, but eventually become less effective:

If there is a set point, I believe it’s not a weight set point but rather a pleasure set point. When you don’t reach the set point, cravings start and when you go over the set point (staying too long at the fair) you get feelings of aversion.

I doubt if the pleasure set point changes very much. People simply switch sources of pleasure. Stop smoking, and you start eating more. Much of the pleasure of being on this diet comes from the pleasure of feeling in control. Once the novelty of control wears off people will have to look for other sources of pleasure or they will go back to getting pleasure from food.

I think this insightful comments carries a useful warning: that behavioral changes such as diets which cut off one source of pleasure may require us to find a way to replace that source of pleasure, or else risk rebounding from the diet and regaining the weight we lost.

The good news here is that there are proven ways to raise our “pleasure” set point.  The bad news is that they require significant and sustained effort – no quick fixes.  And yet it is the most sustainable way to increase pleasure in life.  To paraphrase a saying about fishing sometimes attributed to the Bible: “Give someone a neurotransmitter and they’ll feel good for an hour; teach someone to grow more receptors and they’ll feel good all the time.”

Explanations. The receptor control theory explains a number of observations that cannot be accounted for by classical set point theory:

1. Biology is not destiny. Individuals do differ genetically in their tendency to gain weight or to be prone to addiction or depression.  You are born with a certain density of receptors and this can be influenced further during prenatal and postnatal development.  But it is not the end of the story. The types of foods you eat and the frequency of eating have strong effects on insulin and leptin sensitivity.  Likewise, exercise, hard work and a stoic practices can sensitize your dopamine receptors and make you happier and less prone to depression.
2. Obesity is not a constant. Both the weight gain of individuals as they age, and the obesity epidemic of recent decades are often blamed on “calorie imbalance”: eating too much and exercising too little. But this doesn’t explain why this caloric imbalance is happening now as opposed to earlier. Sometimes the uptick in obesity is blamed on the increasing availability of tasty high-calorie food and a less active lifestyle. But that explanation cannot be right, because there has always been tasty food. And as Kolata has shown, controlled interventions to reduce calories and enforce more activity have a poor track record.  The reason that body weight set points are rising has more to do with changes in the amounts of food and exercise, as it does with specific types of food, eating patterns and exercise–and the long term hormonal influences of these changes on receptor sensitivity.
3. Permanent weight loss is still possible. Granted, most diets don’t work. Quick weight loss diets don’t work because they don’t allow a biologically realistic amount of time for receptors to upregulate; receptor upregulation is a gradual process that requires persistence and effort. Certain diets are quite effective in the short term, including low carbohydrate diets, low glycemic diets, and the Shangri-La Diet (which temporarily suppresses appetite). These diets will temporarily change levels of hormones, neurotransmitters and other signalling compounds to induce satiety and weight loss. However, unless appetite circuits are permanently “re-wired” by upregulating hormonal and neural receptors, weight loss will be temporary.  Appetite will remain vulnerable to coming back like a tiger, and you may return to your old set point weight — perhaps even plus a few pounds.  The best way to upregulate metabolic and appetite receptors is by strenuous exercise, intermittent fasting or deconditioning.  Given enough time, persistent and habitual dietary changes can lead to permanent weight loss, particularly when combined with reduced eating frequency, intense exercise, and deconditioning.

Biological basis for Hormetism. The receptor control theory also provides us with a some biological underpinnings for Hormetism and Stoicism, as advocated in this blog. Hard work –tough, uncomfortable and challenging activities–can lower our metabolic and pleasure set points, helping us to lose weight and making us less vulnerable to addictions, cravings and depression.  What is exciting to me is that this theory may provide a possible biological basis for the psychological Opponent-Process Theory of Richard Solomon.  The basis is located not in transient chemical messengers like neurotransmitter and hormones, but rather in the adpatable receptors located throughout our body on every cell.  These receptors are part of the hardware or firmware of our bodies and brains.   Receptors are a part of us that cannot be changed overnight, but can only be changed with persistent effort.  (And they will not disappear so readily either).

I will be the first to acknowledge that at this point the receptor control theory is just that — a theory.  It has support by scientific evidence, but many questions remain.  And yet it is a productive theory which generates many testable hypotheses.  It provides us with a possible basis for understanding the benefits of less-studied hormetic or Stoic practices such as showering or swimming in cold water, radiation hormesis, or allergen immunotherapy.  Do these types of stress also result in upregulation or downregulation of specific cellular receptors involved in pain perception, cellular repair, inflammation or immune response? Can we measure and better understand these responses at the level of receptors? Are there practical ways to measure the number and sensitivity of our receptors, so that we can track progress? Receptor change is probably only one of many mechanisms that explain hormesis, but it may be an important and underappreciated one.  These questions make good topics for future posts.

Finally, unlike the classic set point theory, the receptor control theory is not fatalistic, but is optimistic:  By combining insights as old as ancient Stoic philosophy with a contemporary scientific understanding of psychological conditioning and the plasticity of cellular signal receptors and receptor circuits, we can work to achieve fitness and weight loss, freedom from addictive compulsions, and chart other major changes in our metabolic and psychological well being.

Models of addiction. There are a number of different views of what addiction is. The medical model views addiction as a disease, focusing on the biological aspects of physical or psychological dependency. This view typically confines the idea of addiction to cases of substance abuse and dependency, and attempts to pinpoint the basis for addiction in terms of changes in brain circuitry and the chemical action of reward neurotransmitters such as dopamine and serotonin. The medical model also highlights the biological reality of withdrawal symptoms when the addictive substance is removed. A second model, the psychiatric model, looks at addiction somewhat more broadly as a manifestation of unresolved psychosocial or emotional conflicts that lead to compulsions or poor impulse control; often this is broadened to include the family, social or cultural context. A third model, which we might call the autonomy model, rejects the medical and psychiatric models as too deterministic and incompatible with the existence of free will.  This model takes addiction to be fundamentally a question of personal responsibility and choice. Finally, behavioral models do not necessarily take a position on the origins of addiction, but look instead at how addictive behaviors can be modified and eliminated. Of course, there are many variations and combinations of these models of addiction.

Varieties of treatment. Depending on which model is favored, different treatments variously emphasize medical detoxification and the use of pharmaceuticals; individual, family, group or residential rehabilitation counseling; recognition of personal responsibility; or various modalities of behavior modification. Under the medical model, pharmaceuticals are often prescribed for detoxification and the relief of cravings.  While drugs may in fact help reduce cravings in the short term, they can create their own problems of side effects and substitute addictions. Antagonist drugs, which block receptors for “reward” transmitters such as dopamine, are often unpleasant and create incentives to quit or circumvent treatment, and they invite relapse once they are discontinued. Typical success rates for drug and alcohol detox rehab programs, which combine medical detox and psychological or psychiatric treatment, have been cited to be as low as 2-20 percent. One such program, Narconon, claims a success rate of 76%, but this figure has been challenged as being vastly overinflated and based upon methodologically flawed statistics. As with many similar programs, Narconon insists on the importance of getting treatment away from the normal work-home environment: :

One thing is for sure if you are trying to break a habit such as drug addiction, a change of environment should be at the top of the list as far as solutions. Due to these factors, attending a drug rehab close to home is seldom the correct treatment option for chronic drug abusers. It is extremely therapeutic to be distanced from the people they used drugs with, drug dealers, and the surroundings that can continue to stimulate their past addictive behaviors.

As we’ll see shortly, it is precisely this key assumption that is questioned by cue exposure therapies.

Behavioral therapies. In essence, behavioral approaches look at addictions primarily as conditioned behavioral patterns that are strongly reinforced, but from which the addict nevertheless still has some motivation to escape. Behavioral therapies tend to divide into two camps: those which employ classical and operant conditioning to directly modify behavior by changing the reinforcement patterns; and those which supplement the conditioning techniques, or replace them entirely, with a cognitive element, following the model of Cognitive Behavioral Therapy (CBT).  The cognitive element typically involves actively thinking about ones behavior, and reflecting on whether or not it is based upon rational or empirically valid assumptions. For example, CBT may treat depression, anxiety, or phobias by challenging an individual to consider whether one’s worst fears are in fact likely to happen, what one is giving up by maintaining the present behavior, and what one stands to gain by stopping it.  Often meditation, mindfulness, and notions of self-efficacy are involved in these cognitive approaches. Examples of the application of CBT to addiction are Alan Marlatt’s Relapse Prevention Therapy and also his Mindfulness therapy; and Aaron Beck’s Cognitive Therapy of Substance Abuse.

However, overcoming addiction may not be all that susceptible to “reasoning” and reflection. Addictive cravings are often incredibly powerful and tend to overwhelm rational thinking.

Cue exposure therapies. There are two very different approaches to treating addiction by behavior modification:  stimulus avoidance and cue-exposure therapies. While they are both considered “behavioral” treatments, they are in fact polar opposites! The stimulus avoidance therapies involve training the individual to avoid exposure to the stimulus. In practical terms, this means abstinence. It  is the approach taken, for example, by Alcoholics Anonymous. A core assumption of AA is: “Once an alcoholic, always an alcoholic”.  Those who take this view claim that it is impossible, or highly risky, for an alcoholic ever to return to moderate drinking. AA has a good success rate, but it tends to require a strong “spiritual” commitment, and can be sabotaged by relapse if the recovering alcoholic or addicts takes even a single drink.

There is an emerging area of research, however, which takes issue with the stimulus avoidance school of thought, and supports the idea that addictions can be replaced by normal responses to behavioral cues, using cue exposure therapy, sometimes called response prevention therapy.  And even more radically, the treatment works best if carried out in the most realistic context of the daily life patterns of the addict.  This completely contradicts the central assumption of Narconon in the above quote!

For a full explanation of the psychological basis and technical terminology of reinforcement theory, I would recommend reading the Psychology page of this blog, which provides useful background on the work of Pavlov and current applications by behaviorists such as Daniels and Pryor in the use of cue exposure as a general method for extinguishing behaviors.  In short, the essence of cue exposure therapy is to extinguish the addictive behavior by allowing the addict to be exposed to normal cues or stimuli that typically precede the addictive behavior, but preventing that behavior from getting underway. This clearly leads to significant discomfort and even withdrawal symptoms in serious cases.  However if repeated frequently enough, and in the presence of a sufficient variety of cues and contexts, cue exposure therapy can be very successful in extinguishing addiction.  Even more importantly, there is evidence that is is successful in preventing relapse over the longer term.

Furthermore, cue exposure therapy is a general approach to addiction treatment. It works not only in treating “chemical” addictions of substance abuse, but addictive behaviors more generally.  There are studies showing its effectiveness with treatment of drug and alcohol addiction, tobacco addiction, and eating disorders. For example, using cue exposure and response prevention, combined with gradualism may be more effective than going “cold turkey” for learning to permanently stop smoking. Other studies show that cue exposure therapy is more effective than a “self control” based cognitive behavioral approach in treating bulimia.

What makes cue exposure succeed? Despite encouraging data of the effectiveness of cue exposure therapies in both addiction cessation and relapse prevention, it is not always successful. A recent review article in the journal Addiction, by Conklin and Tiffany of Purdue, provides an excellent meta-analysis of 18 cue exposure therapy for treating a range of addictions–including treatments for addiction to alcohol (N=5), nicotine (N=5), cocaine (N=1), and opiates (N=6).  The review includes a careful analysis of why cue exposure therapies in many cases fail, why they often succeed, and what specific factors determine their degree success. Conklin and Tiffany not only review the clinical and field studies with human subjects, but also cite the most current animal research on addiction extinguish to buttress their analysis. This is an academic paper, but clearly written and accessible to the intelligent layperson. For anyone struggling with addiction and willing to consider cue exposure therapy, I highly recommend reading this paper carefully to absorb its many insightful lessons.

The cue exposure treatment studies varied considerably in their design and execution. In about half of them (mainly the drug studies), the participants were abstinent during cue exposure.  In one study (with alcohol dependence),  a moderate drinking goal was encouraged by providing “priming” doses of alcohol, with the the prevention of drinking more than one drink, and this behavior was practiced both “inpatient” and as outpatient “homework”.  Cue exposure varied from real “in vivo” cues to surrogate video, audio, and even “imaginal” cues just pictured in the mind.  The frequency of cue exposure varied greatly — from a single cue exposure (e.g. smelling a glass of alcohol for 3 minutes) within a single session, to multiple, frequent exposures per session over 10 consecutive days of cue exposure sessions, to periodic exposure sessions spaced in time over weeks, with follow up over 6-12 months.

In their review article, Conklin and Tiffany identify 4 main “threats to success” (and corresponding success factors) that explain both why cue exposure did not work well in some cases and where it either was, or could be made, more effective.  Before summarizing these success factors, I think it is important to note one key insight they highlight regarding recent learnings from animal research:

Rather than simply trying new things in an effort to discover the optimal parameters for use in cue-exposure addiction treatment, ideas for improving treatment can be directly informed by recent animal learning research focusing on extinguishing learned behavior…ideas about extinction have changed considerably since cue exposure was first introduced as a treatment for addiction. For many years, extinction training was believed to lead to a weakening of the initially condition CS-US association…However current concepts about extinction resemble more closely the original ideas of Pavlov (1927), who postulated that repeated unreinforced exposure to the CS does not break the original CS-US learning, but rather serves to mask it…Therefore, the conventional notion that extinction is unlearning has been replaced with the position that extinction is new learning, that is, during extinction, CS-US learning remains intact, but new associations develop to the original CS. (p. 159)

This is a crucial insight!  The original addictive response to stimulating cues will never die by itself, merely by not reinforcing those stimuli.  Rather, it is important to learn new behavioral responses to those old cues which come to “mask” or dominate the the old responses.  Cue extinction is an active process, not a passive one!

Now let’s turn to the specific threats to the success of cue extinction which have been identified by Conklin and Tiffany:

1. The renewal effect occurs when a behavior is successfully extinguished in one limited context or set of cues, but re-emerges in response to a different context or cues. This is a common problem in treatment, because the treatment context often differs in significant ways from the “real world”.  Conklin and Tiffany give the example of a heroin addict who gets inpatient extinction treatment in a hospital room, but resumes shooting up at home–a different context, with different cues. The same conditioned stimulus (CS)– for example seeing or handling drug paraphernalia, or being stressed–can acquire a different “meaning” in the two different settings. Cues can be rich, subtle and varied: the action of lighting a cigarette with a match, handling of drug equipment, or the smell, the size and feel of surroundings, people, and the time of day. There are a number of important ways to deal with this problem.  First, the extinction training should as much as possible occur in the “original conditioning context”, that is the real-world context in which the addiction was acquired and has been developed.  Second, given the fact that most addictions are reinforced by a rich set of cues and multiple contexts, the extinction training should occur in several distinct contexts, and then re-tested in the original context.  According to the authors, “Apparently, whereas conditioning generalizes readily, extinction is largely context-dependent”. (p. 160).
2. Spontaneous recovery occurs merely with the passage of time, even when a behavior is initially extinguished successfully.  The addiction can re-emerge by itself days, weeks, or months after being apparently terminated. Dealing with spontaneous recovery requires consideration of the “temporal spacing” of cue-exposures. Here, the authors cite a number of animal studies for guidance. In one such study, extinction occurred more rapidly and successfully when the cues were given as a series of short exposures over time instead of as a single “massed” presentation. Other studies found that extinction success was optimized by allowing longer intervals of time between exposure sessions, combined with more frequent in-session exposures. This was also reflected in the human studies. Based on this research, Conklin and Tiffany give the following guidelines:
   • Within each session, the cue should be presented several times to ensure complete extinction of “responding”, defined as as subjective desire or objective physiological or behavioral response
   • Within-session exposures should be separated by enough time to allow some recovery of responding between exposures
   • Enough time should be allowed between sessions to allow for spontaneous recovery of responding, and therefore further extinction at each session
   • The number of extinction sessions needed depends on the individual’s pattern of responding, which can vary considerably among individual subjects
3. Reinstatement occurs after a conditioned stimulus (CS) has been extinguished, by presenting the unconditioned stimulus (US) alone.  For those not familiar with this terminology (which is described in more detail on the Psychology page of this blog), the US is the immediate agent that produces the addictive “high”, e.g. the drug, tobacco, alcohol or food itself, whereas the CS is any cue which becomes associated with it, e.g. seeing or handling a bottle or cigarette, or visiting a bar or drug dealer. So in reinstatement, the former addict has learned not to respond to the environmental context and cues, but for one reason or another encounters the addictive substance in a new context, re-igniting the addiction anew and leading to potential relapse after even a single new exposure.  Here, the research on prevention is very interesting. Relapse in such situations can apparently be prevented or quickly cut off by immediately exposing the lapsed addict to unreinforced exposure to the new context alone (without the US).  So if your addiction to sugar or alcohol is re-ignited by inadvertently or unwittingly consuming a food that stealthily contains this offending substance, expose yourself to eating other foods (without the addictive substance) in the same place and with the same cues, on more than one occasion, and the relapse will be forestalled.
4. Behavioral cue conditioning is one of the more subtle, but insidious threats to successful extinction. If the addiction is based upon classical conditioning (that is the addictive behavior is a direct “conditioned response” (CR) to one or more conditioned stimuli (CS), then deconditioning by extinction training has an excellent chance of success.  However, in many cases of addiction the CS indirectly elicits behaviors that precede the direct addictive response, and these behaviors themselves act as secondary “discriminant stimuli” which provoke the addictive response independently of the CS.  For example, for an alcoholic, the CS may be a bottle of booze. By the principles of classical conditioning, the appearance of the bottle can be extinguished as a cue for the urge to drink (the CR or conditioned response), by exposing the alcoholic to the bottle and not allowing drinking. However, in the normal context, the alcoholic engages in certain active routines or behaviors, such as pouring the alcohol into a glass, handling the glass, drinking from the glass, etc. These behaviors in themselves serve as independent cues, beyond appearance of the bottle itself, that stimulate the desire for the alcohol.  So it is not just the sensory stimuli that need to be extinguished, it is also the behavioral cues.  Overlooking this reality turns out to be a major flaw of many of the less successful treatments reviewed by Conklin & Tiffany. In these flawed treatments, the cue exposure sessions dealt with sensory cues alone. The authors found the best treatments involve extinction of active behaviors.  For example, one study had smokers actually light cigarettes and take non-inhaled puffs.  Another study had heroin addicts go through an actual cook-up procedure and handle all their paraphernalia, without allowing follow-through to actually administering the drug. While to an adherent of the “abstinence” approach such therapies may seem unduly risky, the science actually supports such realism as being the most effective way to immunize an addict against relapse.

There is some recent evidence from a study by researchers at McMaster University and the University of California at San Francisco that takes this approach even further.  In cases where the goal is moderation and not abstinence, it is important the the cue exposure involve actually take small doses (e.g. one drink), while preventing any follow up drinks, to re-train the response.  This is based on observations that addicts or alcoholics respond to a small dose as a cue that “more is coming”. Without this type of conditioning, there may be increased risk of relapse.  Again, “you get what  you train for”.

Conclusions. In short, cue exposure therapies will not work if they are confined to small number of artificial exposures within a single limited context, especially if it is significantly different from the context where the addictive behavior was “learned”.  The exposure should be rich and varied, repeated both within a cue exposure session and at subsequent sessions while allowing an adequate time interval both between in-session exposures and between separate sessions to allow “responding” or partial re-emergence of the desire or craving. Cue exposure therapy should not involve mere passive exposure to sensory cues but should  include a realistic “behavioral” component which is practiced without allowing the reinforcement itself to occur. Finally, it is important to keep in mind that extinction is not a matter of passively “unlearning” an old behavior by just not responding, but actively learning new substitute behaviors for responding to the original cues and contexts; adding a degree of “counter-conditioning” is useful here (see the discussion of counter-conditioning on the Psychology page of this blog.

What does this mean for you? Is there an addictive behavior or a bad habit you would like to overcome?  Are you willing to try cue exposure therapy.  If so, observe and think about the sensory and behavioral cues that precede your behavior and how you could design your own cue exposure sessions to help extinguish the behavior.

What does this mean for me? I stated at the beginning of this post that I would do something unusual. Rather than writing this post purely as a scientific report or as an “advice column” to others, I am going to put it to the test on myself.  In the tradition of self-experimentation inspired by Seth Roberts, I am going to put my money where my mouth is and try it on myself.  I have used cue extinction already as the basis for deconditioning myself from having a strong appetite for food (at certain times of day), for cutting back significantly on certain favorite desserts (such as ice cream), and for giving up caffeinated coffee (but still enjoying the occasional cup of decaf).  However, I retain a certain fondness for alcohol.  I’m not an alcoholic and and don’t believe I have a drinking problem, but I drink more than I would like to and find myself craving certain drinks before dinner almost nightly. My favorite drinks, in order, are: (#1) B&B cognac liquor on the rocks; (#2) Manhattan cocktail; (#3) beer; (#4) red wines, especially Pinot Noir.   About a year ago, I cut back to a frequency of 1-2 drinks per week, but recently this has crept up to a nightly drink, and I find myself really looking forward to it after work.  It is a real pleasure and stress reliever, and I don’t want to cut back, but I know I should.

So you’ll find a record of my experiment, starting today (Thursday, April 14), on my personal page on the Discussion Forum.  At this point, my goal is not total abstinence, but cutting down to a maximum of 1-2 drinks on 1-2 nights per week. Wish me luck!