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.

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.

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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!

1. Flavor-calorie dissociation as advocated by Seth Roberts in his Shangri-La Diet
2. Sensory-specific satiety, as advocated in David Katz’s Flavor Point Diet
3. Tastants, another approach to sensory-specific satiety, as advertised in Alan Hirsch’s Sensa Weight-Loss Program.
4. Odor inhalers, a third approach based on sensory-specific satiety, as described in Alan Hirsch’s book Scentsational Weight Loss, and marketed by him as ”diet pens” offered by SlimScents

At first, some of these approaches appear to be mutually incompatible. The Shangri-La theory argues that strong or familiar flavors enhance appetite when they become associated with caloric foods.  The other three approaches, by contrast, claim that intense flavors or aromas suppress appetite, based upon the principle of “sensory-specific satiety”, whereby an increase in the intensity of a single flavor or odor induces satiety. However, on closer examination, all of the above theories are consistent with one another, as I will try to show. Furthermore, they each provide some useful clues about how to achieve a long term weight loss and relief from hunger cravings by paying attention to the role of flavor and other food cues.  Finally, as I will attempt to persuade you, only one of the above diets is truly a type of Deconditioning Diet that can lead to long term, permanent reduction in appetite, based on the principles of Hormetism.

This post is one of the longer, more complex ones I’ve written so far. It’s almost like a full chapter in a book.  For that, I apologize. But if you hang in there and try to follow the twists and turns in the science, I think at the end of this post you’ll find that certain puzzle pieces start to fit into place, leaving us with a framework that helps us to figure out some truly effective new methods of controlling appetite and weight. If  you want to skip to the punch line, you can find the simple explanation at the bottom of this post, below the dotted line, under the heading “A Unified Explanation of Flavor Control Diets” and “Lessons Learned”.  But for those who want to understand the science, read on….

I’d like to briefly review these weight loss programs and the underlying theoretical explanations for two reasons. First, I think that while the diets are useful, the explanations offered as to why they work are in several instances incorrect. I believe that the insulin response theory of appetite provides a more adequate explanation, and one which resolves the apparent contradiction between the two theories. Second, and more importantly, I think the insulin response theory of appetite, in combination with the philosophy of Hormetism, provides a scientific basis for the Deconditioning Diet.  As detailed on the Diet page of this website, the Deconditioning Diet is a weight loss program that offers the prospect of permanent and lasting changes to appetite and long term weight loss without dependence on consuming or using specific dietary agents or devices, such as is required by all four of the above flavor control weight loss methods.

The Shangri-La Diet. I credit Seth Roberts’ book by this name for first making me aware of the connection between flavor, appetite and weight control.  I tried the diet and it works.  I lost 10 pounds rather easily by using Roberts’ concept of flavorless calories to suppress appetite. Roberts discovered his diet while vacationing in France.  He tried some French sodas with “unfamiliar” flavors and found they suppressed his appetite almost totally. He found himself skipping meals or forgetting to eat, and he lost weight on the trip. He hypothesized that it was the unfamiliar flavors in combination with the calories from sugar that led to his appetite suppression. When he got home, he figured out that consuming sugar water with no added flavor would be as effective and simpler than using unfamiliar flavors.  Consuming daily fructose water left Roberts hungry enough to eat only “about one meal every two days”, and he steadily lost about 2 pounds a week, dropping from 185 to 150 pounds in short order. He satisfied his desire for non-caloric flavors by drinking tea and chewing gum, and his desire for texture by consuming  small portions of crunchy or chewy snacks like apples, nuts, or jerky.

Roberts then generalized his diet to stipulate ingesting small 200-calorie doses of flavorless calories, at least an hour before or after any meal.  “Flavorless” in this case means undetectable by the nose.  The sweetness of sugar appears not to count as a flavor, because it is detected only on the tongue and not by the nose.  (A test of whether something is a flavor is that it will become undetectable if you pinch your nose while tasting.  Sweetness, saltiness, and sourness are detected by the tongue only).  So besides sugars like sucrose and fructose, Roberts found that vegetable oils work well, particularly low flavor oils like extra light olive oil (ELOO) and certain nut oils.  On his website,  Roberts hosts a forum where an on-line community of SLD diet followers have extended the methodology to include variations such as “nose clipping” (wearing a nose clip or pinching your nose to suppress flavors while eating regular foods) or formulating various flavorless drinks and meals.  The SLD diet has clearly been successful for a great number of people,  many who have found it to be the least painless way to regain control of their eating and lose a large amount of weight, with great flexibility, no restrictions on the types of food you can eat, no calorie counting, and no sense of deprivation.

Roberts’ theory of weight control can be summarized as follows:  Foods with a weak flavor-calorie association will lower your body fat set point and cause you to lose weight; foods with a strong flavor-calorie association will do the opposite. He supports his theory of flavorless calories with evidence from the usually disparate fields of weight control (physiology) and associative learning (psychology). From weight control theory, he draws on the lipostatic theory of Gordon C. Kennedy.  Kennedy conducted experiments with rats in the 1950s which suggested that weight or body fat is homeostatically controlled to a relatively constant “set point”. When rats were fed less calorically dense food, they first lost weight, but then adjusted by eating more of the low-cal chow to re-establish their “set point”, just as a thermostat will turn on a heater whenever the temperature of the building drops below its set point. Kennedy’s experiments were backed up by similar studies in other animals and humans. In particular, Roberts cites a series of experiments by Dr. Michel Cabanac, a physiology professor at Laval University in Quebec. Cabanac worked with human subjects, who generally find glucose water pleasant to sip. Cabanac slowly pumped glucose water directly into the stomachs of his subjects, and then had them sip sugar water. For the subjects who had sugar injected into their stomachs, the sipped sugar water became less pleasant, and they felt full. In a follow up experiment, subjects first lost 8 pounds by just eating less of their usual diet, then the glucose injection experiment was repeated.  This time, the injected glucose water no longer reduced the pleasantness of the sipped sugar water, and the subjects remained very hungry. Roberts takes this to indicate that the increased appetite of this second group was caused by their actual weight being below their “set point” weight. In a further experiment, Cabanac found that letting subjects consume as much as they wanted of a restricted bland liquid diet let to significant weight loss without hunger.  And one of Cabanac’s students found even faster weight loss and appetite suppression by directly injecting the liquid nutrition through a stomach tube. This suggested to Roberts that flavors raise set point, and lack of flavor (as in direct injection of sugar or food to the stomach) reduces set point.

From associative learning, Roberts draws upon the very work of Pavlov that I have cited (for different reasons) on the Psychology page of this site.  He cites several experiments that appear to establish the general principle of flavor-calorie associative learning.  In one study with rats, Dr. Anthony Sclafini, a psychology professor at Brooklyn College in New York, allowed rats to drink water with two different flavors.  Whenever they sampled Flavor 1, a caloric starch compound (Polycose) was injected into their stomachs, but when they drank Flavor 2, plain water was injected into their stomachs.  The rats developed a strong preference for Flavor 1, and this preference persisted several days even after the injections were stopped.  Since they could not “taste” the injected Polycose, Sclafini and Roberts take this to provide flavor-calorie associative learning.

Putting these two lines of research together, Roberts concludes that consuming calories with familiar or strong flavors tends strengthen flavor-calorie association and preference for those flavors, and will raise the weight set point, whereas consuming flavorless calories or calories with unfamiliar flavors tends to reduce both the flavor preference and the set point.  Roberts and his followers have used the hypothesized connection between flavor-calorie association and body fat set point to make predictions and extend the diet. For example, Roberts predicted and confirmed that appetite suppression and weight loss can also be achieved by consuming foods with unfamiliar flavors, so one variation of SLD is to add “crazy spices” to foods to break the flavor-calorie association, or by using nose-clipping to suppress detection of flavors while eating.

However, the success of the SLD diet in itself does not prove that Roberts’ explanation for why it works is correct. I believe that Roberts explanation is incorrect for several reasons:  (1) the set point theory is not empirically testable;  (2) Roberts learning theory is based on a misunderstanding of Pavlov’s theory of associative learning; (3) Roberts’ learning theory makes several false predictions and fails to explain other facts about weight loss; (4) there is an alternative explanation for why SLD works that can better explain these other facts about weight loss.  I’ll take up these criticisms in order.

Lipostatic set point theory of weight control. According to Roberts, if you weigh less than your set point, “you will be hungry and think about food” and the bigger the gap, “the more you will think about food, and the more food it will take to feel full when you eat.  It is nearly impossible to weigh much less than your set point for a long time–the hunger becomes unbearable.”  (SLD, p.9) Similarly, if you weigh more than your set point you will not be hungry and “When you eat, you will feel full rapidly.” It is apparently not your weight, but your body fat content, that is compared with a set point. “When your body-weight regulatory system detects that you have less fat on your body than your set point, it makes you more hungry than usual between meals and increases how much food you need to eat to feel full.” (SLD, pp. 41-2)

And yet the lipostatic set point does not seem to operate like temperature set point on a thermostat. Whenever the temperature is below the thermostat set point, the heater turns on immediately, or after a short delay. And whenever the temperature is above the set point, the heater never turns on–until temperature drops on its own, or with the assistance of air conditioning. But this is not the case with body weight “set point”. When you weigh 8 pounds less than your set point, you don’t eat continuously in one session until the set point is reached. Likewise if you weigh 8 pounds more than your set point, you don’t totally stop eating until your weight drops to the set point level. Instead, most people have a certain rhythmic frequency of eating alternating with not eating. Something else regulates this rhythm of meals even when we far from set point. (As I’ll suggest below, that “something” is the hormone insulin).

Roberts acknowledges that set point is not fixed, and he posits that your set point is directly influenced by what you eat. He explains that between meals, your set point goes down gradually, and the higher your set point, the faster it goes down. But, according to Roberts, your weight goes down faster than your set point, which is “why not eating causes hunger–and why diets that deprive you of food don’t work.” Eating foods with flavor-calorie association will immediately raise set point; and the stronger the association, the greater the increase in set point.

But this is an odd sort of set point that is never really set! The very thing that is controlled by set point (eating) itself causes the set point to change. It is as if a thermostat setting were itself influenced by the temperature in the house, rather than by the intentional decision of the house occupants. The set point concept starts look very flexible, with a lot of external influences and circular feedback loops. (It reminds me of how epicycles were added to the Ptolemy’s geocentric theory of the solar system in order to explain the apparent zigzagging of observed orbits of plants and stars around the earth, until Copernicus eventually came up with the simpler heliocentric theory in the 16th century). If set point is always changing, how could you verify this? It just seems like a convenient theoretical entity that can never be proven or disproven. Roberts’ claim that highly flavored caloric foods cause weight gain because they are “high set point foods” is an example of this circular reasoning.

There is also one other weird aspect of the lipostatic theory of weight control.  It seems to commit us to the view that each of us has a “natural” set point weight or fat mass, which we cannot change.  Unless, that is, we following the Shangri-La Diet and we commit ourselves to eating bland foods, at least periodically–forever. If we are born with a “fat” set point weight and eat flavorful caloric foods, we are destined to get fat. Naturally thin people who can eat flavorful foods are just lucky, because…they are born with a low set point.  Somehow, I doubt this.

This does not mean we should throw out the concept of a set point.  We just have to pick a physiologically verifiable set point.  True examples of set points and homeostasis are blood pH and body temperature which are controlled in a narrow range, under normal circumstances. There is not anything that you can do to alter these set points, and nor would you want to do so. Fevers, hypothermia, and ketoacidosis are indicators of disturbance or pathology, and the organism works hard to restore temperature or pH to the healthy set point values in such cases. Furthermore, the physiological basis of these homeostatic mechanisms for regulating body temperature and blood pH are well known. So I think that extending the set point concept to such a variable quantity as body weight is neither legitimate nor useful, and there burden of proof should be on its advocates to demonstrate an empirical basis for it.

Roberts does acknowledge physiology when he claims that set point is related to the concentration of leptin in the in the bloodstream:

In order to regulate the amount of body fat, the brain must be able to know how much body fat you have, just as a thermostat needs a built-in thermometer to keep track of the room temperature. Leptin serves as the brain’s body-fat thermometer: The concentration of leptin in your blood tells your brain how much fat is in your body. Leptin is produced by fat cells. When your body fat goes up, so does the amount of leptin in your blood.  When your body fat goes down, leptin goes down.  (SLD, p. 143)

This is getting closer to a bona fide physiological explanation. In fact, I agree that hormones drive weight control, I just think that Roberts has chosen the wrong hormone. There are two problems with choosing leptin. First, while leptin does play a key role in signalling satiety to the brain, it is not the whole story. First, the leptin signal does not always work. People can become resistant to leptin.  The brain can’t always “hear” leptin even when it is elevated, leading people to overeat. This is especially true with obese individuals.  The leptin signal can also be blocked by ingesting a meal high in carbohydrates, since carbohydrates lead to high triglyceride levels in the bloodstream, and this can block the leptin signal, again leading to overeating. Furthermore, leptin is not the only player in hunger signaling. The brain integrates the signal from leptin with that of other appetite signallers, including hormones such as ghrelin, and neurotransmitters such as neuropeptide Y, serotonin, dopamine and various opioids.  We need to look further up the stream to the root cause of hunger, not the “messengers”.

Another problem with the leptin theory is that is inconsistent with at least two observational facts:

1. The observed variability in body weights in the population. Leptin is known to increase in fat individuals and decrease in lean individuals.  So lean individuals, who have lower levels of leptin, should be hungry and want to eat more, until their leptin reaches a “satiating” level.  However, that would seem to rule out the existence of lean people. Everyone should eat until their leptin level reaches the “normal” level.  And yet that is absurd, because most lean people are not ravenously hungry.  That implies that every individual can have a different “normal” leptin level.  That is in fact the case, but then it removes leptin as a homeostatic regulator of weight or body fat.
2. The suppression of hunger observed during extended fasting. After an initial period of cravings, light-headedness or other hypoglycemic response, people who are fasting for extended periods of 12-24 hours or longer commonly report appetite suppression and a surge of energy.  This cannot be explained by the lipostatic set point theory or Roberts version of it. To repeat what I wrote above, according to Roberts, your weight goes down faster than your set point, which is “why not eating causes hunger–and why diets that deprive you of food don’t work.” But if weight is dropping faster than set point during fasting, your hunger should increase monotonically, that is, it should get steadily more intense, without dissipating.  Yet that is not what happens.  After a period of adjustment, as insulin drops, glucagon rises along with adipose tissue lipase, and adipose tissue begins releasing free fatty acids into the bloodstream, while the liver breaks down glycogen into glucose and proteins into glucose via gluconeogenesis.  So a constant level of glucose in the bloodstream is restored, and there is no sense of deprivation or “unbearable” hunger.  Most people who fast, including myself, find it quite pleasant.  I think the bad rap on fasting comes from people who have not studied the physiology of fasting and either haven’t tried it, or haven’t given their bodies enough time to adapt.

The glucostatic theory. There is a much better alternative to the lipostatic theory of hunger and weight regulation:  namely, the glucostatic theory of Jean Mayer, as it has been developed into a fuller theory of the homeostatic regulation of blood glucose by the hormone insulin. While there are many hunger signaling compounds, ultimately these signals are either responding to or predicting what is happening or likely to happen to blood glucose concentrations. In the glucostatic theory, there is also a set point that controls hunger, and it is blood glucose concentration. According to the glucostatic hypothesis, there is no body fat “set point” that our body attempts to defend, no “natural” level of fatness or leanness. This is evidenced by the fact that it is possible to gain or lose a lot of weight and main these changes. Whether we are fat or lean, our body strives to maintain glucose concentration within a physiologically tolerable range of about 70 to 150 mg/dL. Below that level, hypoglycemia sets off hunger pains, headaches and–in extreme cases–shock and coma. Above that level, there can be both acute problems with high blood glucose and chronic problems with elevated blood glucose, leading eventually to hyperinsulinemia and diabetes. There is an excellent discussion of the glucostatic and lipostatic theories of weight control in Chapter 24 of Gary Taubes’ Good Calories, Bad Calories, delineating further problems the lipostatic theory.

This is not to say that weight is not remarkably stable in most people for long periods of time. But this stability is not the result of homeostatic control.  Rather than being a “set point”, body fat may be a “settling point”.  Taubes is very articulate on this point:

Life is dependent on homeostatic systems that exhibit the same relative constancy as body weight, and none of them require a set point, like the temperature setting on a thermostat, to do so. Moreover, it is always possible to create a system that exhibits set-point-like behavior or a settling point, without actually having a set-point mechanism involved. The classic example is the water level in a lake, which might, to the naive, appear to be regulated from day to day or year to year, but is just the end result of a balance between the flow of water into the lake and the flow out. When Claude Bernard discussed the stability of the milieu interieur, and Walter Cannon the notion of homeostasis, it was this kind of dynamic equilibrium they had in mind, not a central thermostatlike regulator in the brain that would do the job rather than the body itself.

This is where physiological psychologists provided a viable alternative hypothesis to explain both hunger and weight regulation. In effect, they rediscovered the science of how fat metabolism is regulated, but did it from an entirely different perspective, and followed the implications through to the sensations of hunger and satiety. Their hypothesis explained the relative stability of body weight, which has always been one of the outstanding paradoxes in the study of weight regulation, and even why body weight would be expected to move upward with age, or even move upward on average in a population, as the obesity epidemic suggests has been the case lately. (GCBC, pp. 428-9)

In effect, the apparent stability of weight results from a relative constancy in many factors–hormone activation, food intake, physical activity–any change in which can shift this balance to a new stability point.

The glucostatic theory also provides explain how appetite can change on a minute-by-minute basis. Typically, a drop in blood sugar is associated with hunger and the initiation of eating.  While blood sugar can drift down on its own, the more usual scenario is that food cues such as aromas, or the time of day, lead  to a psychologically triggered secretion of insulin are the immediate causes of a dip in blood sugar, with its attendant hunger signals.  This usually occurs at meal times because of prior conditioning.  Blood sugar can also drop when the body is running low on glycogen and is having difficulty switching over to fat or ketones, or when blood sugar is depleted by exercise or other activity that outstrips the ability to resupply glucose from the tissues.

Unlike blood glucose and insulin–which can change by the minute and correlate well with the well known rhythms of appetite and satiety–body fat and body weight change much more slowly, and therefore do not seem to be good candidates for direct control, as required by the set point theory of weight regulation.

Associative learning. There is a second problem with Roberts’ explanation of why the Shangri-La Diet works. One of Roberts central claims is that body fat set point is influenced by flavor-calorie association, and that the strength of the association between flavor and calories comes about by means of associative learning. In this regard, Roberts explicitly invokes Pavlov to explain why the the SLD requires that flavor and calories be detected at separate times:

In Pavlov’s experiments, the bell was the signal and the food was the outcome.  The food was given at the same time the bell was turned off.  Had the food been given many minutes after the bell was turned off, the dog would not have associated them  at all. (SLD, p. 47)

Roberts further supports this contention about timing by citing experiments with rats indicating that “a flavor-calorie association was learned even when there was a thirty-minute gap between eating the flavor source and eating the calorie source” (p. 70), but a one-hour gap was sufficient to prevent such a learned association from forming. The flavorless calorie window of one hour stipulated for the SLD is based on the Pavlovian principle that “the more delayed the outcome, the weaker the association”.

But I believe Roberts’ interpretations and conclusions regarding Pavlov’s finding are not correct here. First, Pavlov did in fact show in his experiments with dogs that a delay between a stimulus such as a buzzer, and a delayed feeding would merely reinforce a delay in the salivation. The dogs would wait the required amount of time:

As his technique became more practiced, Pavlov’s laboratory began investigating the canine sense of time. After a dog was trained to salivate at a flash of light, the delivery of the stimulus was postponed by three minutes. Before long, the dog learned to anticipate the delay. Three minutes after the signal, the animal’s mouth would water. (The Ten Most Beautiful Experiments, p. 132).

But second, note that Roberts in the previous quote is talking about an association between the bell and the food presentation (two stimuli). That is indeed associative learning, because both the bell and the food can be perceived. The bell and food repeatedly occur together, and become psychologically associated.  This association is strengthen considerably by reinforcement.  The bell is a conditioned stimulus (CS) and the food is an unconditioned stimulus (US) and classical conditioning is all about associating CS with US, by virtue of reinforcing the unconditioned response (UR). In this case the UR is salivation and an increase in appetite, and the reinforcement is the rise in the dog’s blood sugar that occurs after it eats the food. (If the food was taken away before being eaten, there would be no reinforcement).

Yet in his explanation of why the Shangri-La diet works, Roberts talks about an “association” between flavor and calories. However it is a misapplication of the concept of associative learning to speak of “associating” a perceivable entity (flavor) with an unperceivable physiological reaction (detection of “calories”). The calories cannot be directly perceived by the sensory apparatus. Rather, the ingestion of food results in a physiological response, a rise in blood sugar, and its further consequence, secretion of insulin. There is a perceivable consequence of the calories (hunger), which is possible to associated with certain stimuli.  But that is not what Roberts is claiming. He says that we learn to associate flavors with calories, not with hunger or satiety. The relationship between a perceivable stimulus and a physiological response, if reinforced, gives rise to classical conditioning.  This is distinct from associative learning, in which two perceivable stimuli become associated with each other when they occur together repeatedly.

Put another way: it is not strictly correct to say that people “learn” to make “associations” between flavors and calories, especially since they are not directly aware of the calories (other than by reading food labels). All we can discern is whether or not the flavorful food provides relief from hunger. Roberts sometimes seems to conflate awareness of calories–a requirement for associative learning–with physiological detection of calories. But physiological “detection” by the digestive system is not associative learning.Strictly speaking, it is not a flavor-calorie association, but rather an association between flavor and the satisfaction of appetite. An even better way is to formulate this as a stimulus-response relationship, since the primary response is physiological and not conscious. In this case direct response to the stimulus of flavor is insulin secretion, and indirect responses are blood sugar and appetite.  Pavlov primarily studied the conditioning of stimulus-response relationships; the associative learning was merely an explanation for how a secondary, conditioned stimulus could become secondarily associated with the primary unconditioned stimulus.

Even if we were to accept Roberts position that unconscious detection of caloric foods by the digestive system is sufficient for calories to play a role in “associative learning”, we are left without an explanation of how calories per se can be detected.  In this regard, the digestive system does not recognize all “calories” as a monolithic unit of food, as Roberts seems to suggest.  His explanation of how low carb and “good carb” diets work overlooks significant differences in how calories in different types of macronutrients interact with the digestive system. He seems to assume the only difference between carbohydrates, proteins and fats is how quickly they are released and detected:

When a food is digested more slowly, the calories in that food are detected more slowly. Thus there is more of a gap between the signal (flavor) and the outcome (calories). I believe this is why low-carb and good-carb diets work: They replace foods  that are digested quickly, such as bread, with foods that are digested slowly, such as vegetables. The foods that are digested more slowly have weaker flavor-calorie associations. They raise your set point less.  (SLD, p. 47)

But this does not seem very plausible.  Low molecular weight oils can be digested and absorbed as least as quickly as most starches. The reason that oils lead to better appetite suppression and weight loss than simple carbs is not that they are detected more slowly, but rather than they induce little or no insulin response. Furthermore, fats will result in increased appetite in weight if they are combined with even a modest amount of carbohydrates, because the insulin response will cause them to become “fixed” with the glucose to form triglycerides in the adipose tissue. It is critically important to consider the types of macronutrients and how the endocrine and digestive system responds to them alone and in combination.

A better explanation for Robert’s one-hour rule is based on the dynamics of insulin secretion, and the way that this can become conditionally mediated via sensory stimulation of the vagus nerve . When correctly understood in terms of insulin response, the one hour rule should be changed to an asymmetric rule.  In fact, one should only need to wait about 15-30 minutes after ingesting non-caloric flavors before consuming calories, but depending on the meal size, one may need to wait an hour or more before consuming flavors after eating.  This is because the pre-prandial insulin response is shorter and smaller than the post-prandial insulin response.

In fact the one-hour rule must be differentiated even further, based on the macronutrient composition of the calories, and it leads to a number of predictions that diverge from the SLD:

1. Wait at least 15-30 minutes after a flavor or aroma before ingesting carbohydrate containing foods. (This is to allow the pre-prandial insulin response to subside, and blood sugar to renormalize).
2. Wait at least an hour after consuming flavorless carbohydrate-containing foods before ingesting flavors. (This is because the post-prandial insulin is much larger and takes longer to return to baseline than the transient flavor-induced pre-prandial insulin response).
3. The same rules apply to meals which contain large amounts of protein.  Protein is much less insulinogenic that carbohydrates, but large protein meals and certain types of protein are insulinogenic.
4. You can eat fats and flavors together without any worry, because fat is not insulinogenic alone–it requires the presence of a little carbohydrate or a lot of protein to be removed from the bloodstream by insulin.

The flavor-insulin response, which is mediated by the tractus solitarus in the brain and the vagus nerve, is a conditioned response.  It will be strengthened whenever the flavor cue is concurrent or closely followed by a the ingestion of insulinogenic foods, foods which in themselves produce an insulin response when detected by the glucose receptors in the stomach and intestines. Essentially, the flavor-insulin response is a predictive response that readies the digestive tract for food that is coming, by making the food more absorbable. Secreting pre-prandial insulin for a pure fat meal or a small protein meal has no value, and that conditioned response will tend to extinguish. So that leads to another set of predictions. In particular, despite what Roberts claims, fats and sugars should work very differently in the SLD. So here are some predictions made by the insulin-regulated glucostatic theory of hunger, all of which are either not predicted by SLD or are diametrically opposed to what SLD would predict:

1. Consuming pure fats like olive oil or heavy cream should suppress appetite even if they are flavored. This only works, however, if no more than a trace of carbohydrates or proteins.  (This works because fats are noninsulinogenic).
2. Increasing the dose size of oils even to large doses should increase appetite suppression
3. Increasing the dose size of sucrose or glucose beyond the minimum dose, should reduce appetite suppression.  A small amount of sucrose or glucose increases satiety because it raises blood sugar slightly, and flies “under the insulin radar”.  Insulin is not secreted until blood sugar rises above a certain threshold, typically 120 mg/dL or so.  But once it exceeds that threshold, insulin kicks in, and blood sugar drops.
4. Sipping sucrose or glucose slowly will maintain appetite suppression.  If this is done slowly enough, the addition to blood sugar just balances out the amount of blood sugar consumed to meet metabolic needs.  But this is a careful balance.
5. Increasing the dose of fructose, xylitol, erythritol, or other non-insulinogenic sugars should suppress appetite at any dose.

Prediction 4 is consistent with SLD. Predictions 2 and 5 are consistent with SLD, but not predictable from it. Predictions 1 and 3 are contrary to the fundamental assumptions of SLD, and would not be predicted by it.

For anyone who is interested in subjecting SLD to a test, I would be interested in their experience in attempting to verify or refute the above predictions, especially 1, 2 and 3.

The Flavor Point Diet. (FPD). This diet, created by David Katz, is based on the concept of “sensory specific satiety”. Eating a meal with flavors in multiple “competing” categories such as sweet, salty, or savory, somehow stimulates the “appetite center” of your brain, causing overeating. Limiting the flavor categories in a meal or snack to one or two flavor types makes it easier–more rapidly and with less food– for your brain and stomach to reach the “flavor point”, a state of satiety that causes you to stop eating, with less food. This concept is reflected in the popular notion of “multiple stomachs”, whereby you can feel stuffed after eating one course of a meal, but you often seem to find additional appetite for dessert or something different.  The FPD advises you to restrict the number of simultaneous flavors within a meal, but overcomes the potential boredom by allowing you to eat a variety of flavors over the course of a day or week–just not “excessive variety” all at one time.

Katz bases most of his case for sensory specific satiety on the way in which flavors stimulate the production of neurochemicals that activate the hypothalamus:

As soon as you taste food, the sensory information registers in the hypothalamus in the brain, which, depending on the flavor of the food, sends out signals to eat more or less.  Because of this sensory relay system, the appetite center in your hypothalamus can become aroused–and in some cases overly aroused–by how a food tastes. (FPD, p. 4)

As soon as you bite into any food, sensory stimulation of nerve endings on the tongue leads to the release of a number of chemicals, including opioids, into the bloodstream.  You release more opioids–the body’s natural version of drugs like morphine–when you consume foods high in sugar and fat, creating a powerful, neurochemical drive to overeat those foods.  These opioids and other chemicals enter the bloodstream and carry their messages to the hypothalamus, which sends out yet another set of chemicals to regulate appetite. The more flavors your taste buds register, the more stimulated the hypothalamus becomes, releasing the hunger-promoting neuropeptide Y. When you taste a lot of flavors at once, the brain releases a lot of neuropeptide Y.  Meanwhile, in response to the smell and taste of food, your stomach produces the hormone ghrelin, which also stimulates appetite.  It continues to produce this hormone until you eat enough food to literally fill your stomach and stretch the stomach wall. Farther down the line, in your intestines, levels of several hormones rise to varying degrees–depending on the nature of your meal–either inducing more hunger or turning off hunger. (FPD, p. 4-5)

Katz claims that by “organizing” the flavors in our diet, we can manipulate this chain of chemical and  signals and “subdue the appetite center in your brain sooner, before you’ve overeaten.” (p. 9) Katz also does acknowledge a role for insulin in controlling blood sugar, and points out that fast carbs cause a rapid blood sugar surge and an insulin spike which tends to overshoot and lead to a drop in blood sugar, whereas low glycemic carbs like oatmeal result in a lower rise in blood sugar, a slower release of insulin, “no rapid surge and dip in blood sugar levels” and sustained satiety.  But he does not make any direct connection between flavor and the insulin response, putting the onus on the neurochemical triggers like opioids, neuropeptide Y, and ghrelin.

The FPD establishes how flavors can begin a cascade that induces appetite. Katz is probably correct that the effects of individual flavors have a saturating effect on this response, and that the response can be increased by combining multiple flavors. I think that Katz overstates the role that neurotransmitters and leptin play in hunger and appetite.  Neurotransmitters and leptin are are important as primarily signaling compounds to the brain, but they are not the primary causal agent in that chain. Insulin is much more directly involved in the control of appetite, because it is insulin that reduces blood sugar to physiologically unsustainable levels in the first place, and the signaling compounds are merely the messengers. Blaming these signalling compounds for hunger is like blaming a witness for the crime. Perhaps neuropeptides and leptin can signal hunger without concurrent insulin response. I think this is unlikely, but if it occurs, I suspect it is because these signals have independently become classically conditioned to respond to flavors and other food cues that have become associated with the presence of food. As with insulin, these neurotransmitter responses to sensory stimuli can be deconditioned upon experience. However, Katz treats the neurochemical responses to flavors as “hardwired”, overlooking the fact that they are learned or conditioned responses.  The responses will strengthen if reinforced by eating food that increases blood sugar, and will weaken if not reinforced. His claim that sugar and fat alone cause the release of opioids into the bloodstream is not documented and seems unlikely. The tongue does not detect sugar and fat directly. In fact, some neurological research by Woolley et al at UCSF indicates that it is flavors, and not the macronutrient content of foods, that stimulate opioid secretion by the nucleus accumbens in the brain. To the extent that the hypothalamus is engaged, it requires a detectable signal such as flavor.  As Teff showed (see Diet page), the tractus solitarus will trigger the vagus nerve to secrete insulin only in response to flavor and scents that it has learned and expects to be associated with blood-sugar raising foods.

Sensa tastants.  Closely related to the Flavor Point diet is the use of tastants as Alan Hirsch has developed for his Sensa Weight Loss Program.  The Sensa tastants are intense non-caloric flavors that are sprinkled on foods to enhance flavor intensity.  The tastants are matched the flavor class of the foods: savory tastants are sprinkled on savory foods, while sweet tastants are sprinkled on sweet foods. The principle of sensory-specific satiety is identical with that of the Flavor Point diet. One is still advised to eat only one or two “flavor categories” of food at a meal. The advantage of Sensa over FPD, perhaps, is that the satiating “flavor point” is reached earlier in a meal, with less food and fewer calories consumed than otherwise.  It seems to me the the same result could be achieved by spicing your savory foods and adding non-caloric sweeteners to your desserts.

As with FLP, however, tastants will do nothing to fundamentally alter or extinguish strong flavor-insulin responses. So one remains vulnerable to a strong appetite returning when combining foods, and has to observe the principle of limiting the number and variety of flavors at any given meal.

The bottom line, with both FLP and Sensa, is that by confining yourself or intensifying a single flavor, you allow the insulin response to that specific flavor to saturate earlier, thereby limiting the appetite-inducing property of insulin.  If you were to add more successive different flavors, you will tend to stimulate separate flavor-detection pathways and add another wave of insulin secretion and stoking of appetite.

Odor inhalers (Scentsational Weight Loss). Direct exposure to saturating levels of food aromas is yet another way to exploit the sensory specific satiety mechanism. Even though it exploits the same mechanism, it is in an entirely different class and–as I will argue–odor inhalers have the potential to engender long term appetite deconditioning and weight loss.

Alan Hirsch describes his discovery of this phenomenon in his book Sensational Weight Loss (SWL), and the same concept is exploited in the commercial “diet pens” sold by SlimScents. There are a number of other related pens and inhalers marketed as “aromatherapy”. Hirsch reports a remarkable conclusion from his six month study of the use aroma devices for to quell appetite and spur weight loss. The study included 3193 participants, 86% of whom were women, and most of whom were significantly overweight (average weight = 217 lb.). Participants were given small odor inhalers, similar to lipstick dispensers, containing pleasant smelling substances. Three aromas were used: green apple, peppermint, and banana. Hirsch found that varying the aromas was more effective than sticking with the same aroma. Participants were asked to open and sniff the aromas whenever they got hungry–three sniffs in each nostril. But otherwise there were no forbidden foods or other dietary restrictions. The results were impressive. The average weight loss was 5 pounds per month.  Some people lost more than 100 pounds over the six month study. What is especially interesting to me, however, is that there was a permanent deconditioning effect, along the lines of the Deconditioning Diet (see Diet page).  Here are Hirsch’s comments regarding “deprogramming” of the participants’ learned responses to flavors, leading to long-term changes in eating habits:

Just as we have learned to respond to the smell of certain foods by feeling hungry and wanting to eat, we can, in a very real sense, “unlearn” or deprogram ourselves. For many people the smell of any food triggered hunger. Smell a doughnut, salivate; smell a pizza, and the stomach growls. Actually, most of us experience this much of the time; but in the overweight person, this conditioned, or learned, response can be quite. powerful. It’s exciting to realize that people can recondition themselves to smell an odor and not respond with hunger. In the absence of a food associated with the smell, hunger disappeared, the desire to eat subsided, and a pattern was broken. In many cases, this was a long-standing pattern that was broken during the six month study. (SWLP, p. 33-4)

Further evidence of a long term change was reflected in the frequency of use of the odor  devices during the study. At the beginning of the study, participants reported needing to sniff 200 times a day or more; by the end of the study, only occasional sniffing was needed to keep appetite in check. So the the aroma devices don’t themselves become habit forming–the dependence actually decreases over time as new eating habits are consolidated.

In Chapter 4 of Scentsational Weight Loss, Hirsch provides some additional advice, namely that we pre-saturate our satiey centers by sniffing our meals before the first bite to letter the odor molecules fully stimulate the olfactory bulb.  He recommends that we slowly chew and savor the flavor of each bite in order to “fool” the hypothalamus into “believing that more food has been ingested than is actually the case. He also recommends eating food warm or hot to maximize the aroma, adding spices whenever possible, and choosing the more strongly flavored versions of foods.  ”For example, if you eat popcorn, eat the cheese-flavored varierty, or choose an onion bagel over a plain one.” (SWLP, p. 62).

On the face of it, this advice is diametrically opposed to that of Seth Roberts’ Shangri-La Diet!  Roberts argues that blander foods induce weight loss, whereas Hirsch is arging for more intensely flavored and spiced foods. Who is right and what gives?

Here is where all three diets — SLD, FPD, Sensa, and SWL– come together.  After promoting the enhancement of flavor, Hirsch adds:

Try limiting your food choices at any one meal. We still encourage variety, but not necessarily all at one time. We have found that people who want to lose weight should eat only two or three different foods during a meal rather than eating a little bit of many foods…Avoid buffet tables and “all you an eat” food bars. Even salad bars can be dangerous…Even with a smell device, too many selections and unlimited choices spell potential overeating. (Sensa Weight Loss Program, p. 63-64)

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A Unified Explanation of Flavor Control Diets. Here is my summary explanation that can account for the observed effects of all four dietary approaches:  Familiar flavors can induce a pre-prandial insulin response which leads to increased appetite and weight gain. This preprandial insulin response saturates separately for each basic flavor type (savory, salty, sweet, etc.). This saturating pre-prandial insulin response is is a learned response, and one that is reinforced only if it results ultimately in a rise in blood sugar and psychological satiation. If that flavor or aroma is not followed by more eating, it will eventually diminish or extinguish as a cue.

Here then is how this explains each of the four flavor control diets:

1. SLD explanation. Eating foods that contain carbohydrates (and to a lesser extent, proteins) with strong, familiar flavors will lead to a rapid pre-prandial insulin response which may be enough to cause a dip in blood sugar, stoking hunger and leading to further eating. Eating a small amount of bland or flavorless carbohydrate will satisfy hunger by slightly raising blood sugar, and will induce only a small post-prandial insulin response, insufficient to cause a rapid decline in blood sugar, so appetite will remain suppressed.  While SLD keeps insulin in check, it does so only so long as flavor cues are not present. But SLD does nothing to weaken the connection between familiar flavors stimuli and their insulin response, it merely eliminates the stimuli.  One would expect appetite to return when the familiar flavors are re-introduced.
2. FPD explanation. Eating foods with familiar flavors will induce two insulin responses:  a small pre-prandial response and a larger post-prandial response.  However, the pre-prandial insulin responses for that flavor peaks within about 4 minutes after exposure, and sensory detection of that flavor will rapidly saturate.  After it saturates, any further exposure to that specific aroma (or aroma class) will not induce any further insulin response for an extended period of time — up to about an hour. However, introducing new flavors, aromas or other food cues will cause additional secretion of insulin, increasing appetite. The more intense the flavor or aroma, the faster the saturation.
3. Sensa explanation.  The explanation for Sensa is the same as that for the FPD.  Activation of a sensory response to a flavor will induce a small and rapid pre-prandial insulin response. For a single flavor or aroma class, the detection of that flavor will saturate after a certain amount of time, after which it will not prompt any further insulin response.  If multiple aromas are sniffed, then all those smell receptors will become saturated, after which any further pre-prandial insulin response will become muted. Since the Sensa tastants contain no or minimal calories, they provide a way to reach flavor saturation faster, with fewer calories.  In that way, the use of tastants is more effective than the Flavor Point Diet, since fewer net calories are consumed while satisfying one’s appetite.
4. SWL (odor inhalants) explanation. With sensory-specific satiety approahes like FPD and Sensa, the stimulus-response relationship between flavor and pre-prandial insulin response is reinforced. The stimulus may saturate, but the connection with the insulin response remains in place, so that at subsequent meals, the flavor will induce pre-prandial insulin.  However, with SWL, the relationship between flavor and pre-prandial insulin is not reinforced, so it extinguishes!  This is a crucial difference. For this reason, SWL is actually a deconditioning diet that results in long term changes in the flavor-insulin response that suppress appetite and lead to weight loss.  Eventually, the aroma inhalers are no longer needed, or only rarely, to maintain the “deprogramming” that Hirsch alludes to.  By contrast, SLD, FLP and Sensa are not deconditioning diets, but merely methods of suppressing or limiting appetite that work by either minimizing or saturating the stimulus of food cues, but doing nothing to weaken the flavor-insulin response.

Lessons learned. Where does this leave us?  There is a lot to be learned from all four flavor control diets. Flavors and aromas that become associated with foods, particularly carbohydrate-containing foods, strengthen the insulin-response to those flavors and aromas, increase appetite, and tend to increase the consumption of those foods, leading to weight gain. This insulin response and the resulting appetite can be significantly dampened by limiting the variety of flavors while eating.  However, a much larger benefit is possible by using flavors to decondition your appetite:

• You can expose yourself to flavors without carbohydrates or other insulinogenic foods and this will dampen the flavor-insulin response, and lead to a decrease in appetite that is induced by food cues.
• By exposing yourself to a variety of flavors or aromatic stimuli without eating, you will saturate a fuller range of satiety centers and even more effectively block an insulin response.  Sniffing a variety of aromas of different types–savory and sweet– without eating can be helpful in curbing appetite.

These findings have been incorporated into the second phase of the Deconditioning Diet, as described on the Diet page in this website.

Please leave a comment.  You can also check out (and maybe start) a discussion on the Diet Forum linked to this blog.