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.

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Consider the following ten situations:

1. Drug addicts, before becoming addicted, experience the euphoria of a drug with few negative consequences. Over time, however, they develop a tolerance for the drug, requiring increasing doses to get the same high.  At the same time, their cravings and distressful feelings increase when going without the drug, leading to increased in withdrawal symptoms and a cycle of increasing drug use.
2. Firefighters and emergency room doctors have stressful jobs, but many find themselves experiencing an irresistible rush and heart-throbbing exhilaration from these fast-paced occupations.
3. New lovers, after a honeymoon period of initial infatuation, often experience a drop-off in affection, leading to dissatisfaction, fights, and sometimes breakups.  When reconciling after the breakup, they experience renewed closeness for a period of time. Typically, the more intense the infatuation, the greater the strife and negativity during the falling out periods.
4. Marathoners and other runners often experience a “runner’s high” which builds up during longer, more strenuous runs, and can extend for hours or even days after a run. Runner’s high has been associated with release of endorphins, a natural “opiate” produced by the body.
5. Infants who are given a bottle and start sucking on it experience pleasure.  But if the bottles are removed before the infants have finished feeding, they universally cry.  And yet they would not have cried if the bottle had never been given.
6. Depressed adolescents often resort to “cutting”, a form of self-mutilation that introduces some pleasure or even a high into their otherwise sad or pleasureless day.  They often find the need to increase the cutting to maintain the pleasure.
7. Scratching an itch generally relieves the itch and can be pleasurable, but often this ends up making the itch more intense and, after repeated itching, even painful.
8. Horror movies, which initially are disturbing or even terrifying, can become addictive
9. Politicians and executives in positions of power come to crave the power.  When they are out of the limelight, they experience a letdown, boredom, or even depression.  Upon retirement, this depression can lead to poor health or shortened longevity.
10. People who donate blood frequently report a sense of well being and pleasure that cannot be explained in terms of the blood removal itself.

Can you see the pattern?  In the odd-numbered examples above, pleasure turns to pain; in the even numbered examples, pain becomes pleasure. And in all cases, the effect intensifies with repetition. But why does this occur?  One possible explanation for these types of situation is described in William Irvine in his book “A Guide to the Good Life”:

The psychologists Shane Frederick and George Loewenstein have studied this phenomenon and given it a name: hedonic adaptation. To illustrate the adaptation process, they point to studies of lottery winners. Winning a lottery ticket typically allows someone to live the life of his dreams. It turns out, though, that after an initial period of exhilaration, lottery winners end up about as happy as they previously were. They start taking their new Ferrari and mansion for granted, the way they previously took their rusted-out pickup and cramped apartment for granted. (Irvine, p. 66).

Hedonic adaptation is the experience of “getting used to” a good or pleasurable thing until one returns to a state of relative indifference or equilibrium, feeling about the same as one did beforehand. As I describe in more detail on the Stoicism page of this blog, Irvine goes on to point out how the Greek and Roman Stoics were able to combat hedonic adaptation by practicing techniques such as “negative visualization”, in which they regularly took time to vividly imagine loss of people, relationships and possessions they held dear, so they could better appreciate what they had.

Hedonic reversal and habituation. While hedonic adaptation of this sort certainly exists, the ten situations I listed above are quite different than than that of the lottery winner that Irvine describes. My ten situations do not involve a return to homeostasis or equilibrium. They involve a total switch, what I will call hedonic reversal. Pleasure becomes pain; pain turns to pleasure. This is the phenomenon that Richard Solomon tries to explain in his paper.  Solomon quotes Plato, who may been the first to describe true hedonic reversal and puzzle over it:

How strange would appear to be this thing that men call pleasure! And how curiously it is related to what is thought to be its opposite, pain! The two will never be found together in a man, and yet if you seek the one and obtain it, you are almost bound always to get the other as well, just as though they were both attached to one and the same head….Wherever the one is found, the other follows up behind. So, in my case, since I had pain in my leg as a result of the fetters, pleasure seems to have come to follow it up.

In hedonic reversal, a stimulus that initially causes a pleasant or unpleasant response does not just dissipate or fade away, as Irvine describes, but rather the initial feeling leads to an opposite secondary emotion or sensation. Remarkably, the secondary reaction is often deeper or longer lasting than the initial reaction.  And what is more, when the stimulus is repeated many times, the initial response becomes weaker and the secondary response becomes stronger and lasts longer. This is what happens quite clearly in the case of addiction. After repeated administration, the original dose no longer gives the same high, so it must be increased to achieve that effect. In addition, as time goes on, abstaining from the addictive dose becomes more difficult, while cravings, anxiety and depressive feelings increase. The mirror image of this addictive pattern is apparent in the case of endorphin-producing athletic activities like running, or thrill-seeking pasttimes like parachuting. Solomon reports on a study of the emotional reactions of military parachutists:

During the first free-fall, before the parachute opens, military parachutists may experience terror: They may yell, pupils dilated, eyes bulging, bodies curled forward and stiff, heart racing and breathing irregular. After they land safely, they may walk around with a stunned and stony-faced expression for a few minutes, and then they usually smile, chatter, and gesticulate, being very socially active and appearing to be elated….The after-reaction appears to last about 10 minutes…After many parachute jumps, the signs of affective habituation are clear, and the fearful reaction is usually undetectable. Instead, the parachutists look tense, eager or excited, and during the free-fall they experience a “thrill”. After a safe landing, there is evidence of a withdrawal syndrome. The activity level is very high, with leaping, shouting…and general euphoria. This period, often described as exhilaration, decreases slowly in time, but often lasts for 2-3 hours. Indeed, I was once told by a sport parachutist…that his “high” lasted 8 hours. A new, positive source of reinforcement is now available, one that could never have eventuated without repeated self-exposures to an initially frightening situation to which the subject then becomes accustomed. (Solomon, pp. 693-8)

Thus, both the addictive pattern and the thrill pattern share the features of hedonic habituation (reduced intensity of the primary response) and hedonic withdrawal (heightened intensity of the secondary, opposite response). In surveying and studying a wide range of such experiences, Solomon found a common pattern of hedonic contrast, which he represented as follows:

baseline state → State A → State B

State A is the initial emotional or “affective” response to a stimulus, which can be either pleasant or unpleasant.  Typically, the first time a novel stimulus is applied, the primary or State A response is most pronounced at the outset and then tapers to steady level as long as the stimulus is maintained, as shown below in Figure 4.  For example, exposure to the heat of a sauna or hot tub may cause an initially hot or burning sensation, which diminishes somewhat over time. Once the stimulus is removed, the sensation is replaced by a contrasting sensation or affective state, the after-reaction, or State B.  State B is opposite in hedonic character to State A. If one is pleasant, the other is unpleasant, and vice versa. Initially, and after the first few stimulations, State B typically has a much lower intensity than State A, but often lasts longer in duration, before it eventually decays and returns to the baseline state.

What Solomon noticed is that after many repeated stimulations, the intensity of State A typically diminishes, both in peak intensity and steady state intensity. This is the hedonic habituation effect, also called “tolerance”, and it is seen with both pleasant and unpleasant affective reactions. The only way to increase the intensity of State A is to increase the magnitude of the stimulus. At the same time, with repeated exposures, the secondary affective State B often intensifies and lasts longer. This is the hedonic withdrawal effect. This combination of habituation and withdrawal effects is shown in Figure 5:  For addictions, the pleasurability of the stimulus diminishes with time and the unpleasant withdrawal grows in both intensity and duration. For the thrill-seeking or excitatory pattern, the stressfulness or unpleasantness of the stimulus is reduced with repetition, while the  ”withdrawal” becomes more pleasant and lasts longer, before returning to baseline.

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The opponent-process theory. So far, all we have presented is a qualitative description of some common patterns of sensory or emotional response, without any real explanation for why these patterns occur as they do. But Solomon’s real innovation is that he can explain these patterns by decomposing them into more elemental underlying biological processes. His central insight is that the nervous system is organized in such a way that any sensory or emotional response can be decomposed into two concurrent processes. The State A response diagrammed in Figures 4 and 5 above is in reality a composite of two complementary physiological processes:

• a primary process “a”, which is the direct observable response to the stimulus; and
• an opponent process “b”, which acts to inhibit or counteract the primary process.  It occurs at the same time as the primary process, but is not always evident or easy to perceive.

To understand how these processes actually work in practice, let’s look more closely at Figure 7 below. The opponent process “b” actually begins shortly after the initiation of the primary process “a” and acts to dampen it during what we observe as State A. Because “b” is both smaller and opposite in effect to “a”, it acts to reduce the net impact of “a”.  That explains why the intensity of the A process is greatest at the outset, but drops as the stimulus in continued.   According to Solomon, for a novel stimulus the “b” process is smaller and more sluggish than the “a” process.  It is slower to built to its steady state level (asymptote) and slower to decay after the stimulus stops.  This is shown in Panel A of Figure 7:

So what happens to bring about habituation after many repetitions of the stimulus, when the stimulus is no longer novel? According to Solomon, the primary “a” process remains unchanged in response to the stimulus.  What changes with repetition is the opponent process “b”.  As depicted in Panel B of Figure 7, after many stimulations:

• it intensifies
• it starts earlier (reduced latency period)
• it decays more slowly

The net impact of these changes in the opponent process is to progressively dampen the magnitude of State A and increase the speed, magnitude and duration of State B.  Thus, without any changes in the primary process, these changes in the opponent process can fully explain the increase in both tolerance and withdrawal, as shown in Figure 7.

Biological basis. Opponent processes are not just some clever hypothetical construct that Solomon came up with out of thin air. These kinds of inhibitory processes are common in biological systems.  For example, many or perhaps most neurotransmitters, hormones, and biological receptors have corresponding opposites, which act to inhibit or moderate the primary response. These inhibitory processes serve a useful biological control functions by preventing over-reactions to environmental disturbances. They form the the biological basis of systems of homeostasis, systems that enable organisms to resist or adapt to disturbances to their steady functioning.

Solomon’s opponent-process theory also identifies several key factors that can strengthen or weaken the opponent “b” process.  His paper summarizes some very clever animal research on distress behavior in ducklings, from which he deduced that the opponent process can be strengthened in three primary ways:

• increasing the intensity of the initial stimulus exposure
• increasing the duration of the stimulus
• shortening the interstimulus interval (the time between stimulus exposures)

Interestingly, merely repeating the stimulus, in and of itself, had no effect on strengthening of the opponent process if the stimulus was too weak or too short, or if the interstimulus interval was too long.  In particular, he found that, depending on the inherent duration of the opponent process, the interstimulus interval had a major effect on whether or not the opponent process will increase in strength.  According to Solomon

The critical decay duration is that disuse time just adequate to allow the weakening of the opponent process to its original, innate reaction level. If reinforcing stimuli are presented at interstimulus intervals greater than the decay duration, then the opponent process will fail to grow. (Solomon, p. 703)

Each opponent process has an inherent decay behavior, that is, a rate at which it fades away.  This will depend on the specific physiological and biological underpinnings of that process.  On a biochemical level, for example, this decay duration may depend on the half-life of the neurotransmitters, hormones, or receptor behavior involved.  It will surely also involve higher order processes which relate to the nervous system and psychological conditioning of the individual.  Figuring out the decay duration of various opponent processes should be a matter open to empirical determination.  It can be approached both by psychological investigations on others (or on oneself), and also by looking into the underlying physiological and biochemical mechanisms.

The final element of Solomon’s theory is a phenomenon he calls “savings”.  Although opponent processes can be weakened or faded away by avoiding the stimulus for an extended period of time, that does not mean they leave no memory traces. Studies show that these opponent processes are more quickly reactivated the next time they are re-stimulated. Reflexes and emotional reactions build up more quickly when reactivated than they did with the initial stimulation. According to Solomon,

Such a phenomenon is not unexpected. In alcohol addiction, for example, the abstainer is warned that one drink may be disastrous, and the reason is the savings principle. The reexercise of alcohol’s opponent-process system strengthens the withdrawal syndrome very rapidly and sets up the special conditions for resumption of the addictive cycle. Cigarette smokers report the same phenomenon: Readdiction to nicotine takes place much more rapidly than does the initial addiction. (Solomon, p. 703)

This savings effect also applies to positive opponent effects, such as the exhilaration experienced by skydivers or runners when resuming their thrilling or strenuous activities after a hiatus.  Understanding this effect is important in designing strategies for avoiding or minimizing the negative effects of relapse, as will be discussed below.

Put into simplest terms, the opponent-process theory explains the psychology of addiction and thrill-seeking in terms of the strengthening of inhibitory processes.  These inhibitory processes  get stronger when stimulation of a primary emotional response is sufficiently intense, sustained and frequent.  They become evident only when there stimulus and the primary processes are not present, and typically last for some time afterwards.   On subsequent re-exposure the stimulus, opponent processes often reactivated more quickly.

Is this a biologically realistic explanation?  Perhaps Solomon has not generated a broad enough set of hard physiological data to conclusively prove his hypothesis.  However, there is still a strong case in favor of it. First, his hypothesis provides a model which offers a coherent and consistent explanation for a wide range of  sensory and emotional behaviors for which there are few other good explanations. Second, there one application of the Opponent-Process theory–to an area unrelated to emotions–which has already been empirically verified:  the explanation of color perception. It is worth spending a paragraph on this because it provides some insights into the biological reality of this theory.

The opponent-process theory of color vision. Until the late nineteenth century, the primary theory of color vision was the trichromatic theory, which held that color perception was the result of the stimulation of three different types of cone receptors in the retina of the eye.  In 1892, Ewald Hering first proposed the opponent-process theory of color vision. He observed that any color can be uniquely analyzed in terms of the colors red, yellow, green, and blue, and noted that these four primary colors exist as the complementary pairs red-green and yellow-blue. Hering’s theory accounts for how the brain receives signals from different kinds of cone cells and processes and combines these signals in real time. The opponent-process theory of color vision received further support in 1957 in studies by Hurvich and Jameson, and in 2006 by Liapidevskii. Some of the most compelling evidence for the theory is the phenomenon of complementary color after-images, which cannot be explained by the tricolor theory.  You can demonstrate this for yourself by staring at the red dot in the middle of the image below for 30 seconds without letting your eyes drift from the center; then look at a blank white sheet and you will see the image with a more familiar set of colors. (It may take a while for the image to develop).

Looking at the colors under bright light and for longer periods enhances the opponent (inhibitory) processes in the receptors, which intensifies the after-images, just as one would predict based on the principles Solomon found for sensation and emotion.

Consider the similarity between this contrasting after-image response to visual stimuli and the emotional or affective responses that that Solomon found in his animal studies.  The sensory after-images may be less intense and of shorter duration, but the principle is the same, and both phenomena illustrate how opponent processes can arise within our nervous systems. Beyond the processing of simple nerve signals, such as those involved in visual sensory perception, the opponent process theory can account for psychological processes of increasing complexity and at multiple levels, based on the well established fact that the brain is able to integrate sensory information by adding and subtracting different excitatory and inhibitory inputs from different receptors and neurotransmitters.

Practical applications.  Besides explaining common sensory and emotional reactions, I believe the opponent-process provides some very practical guidance for how we can use pleasant and unpleasant experiences to our advantage.  This guidance can be boiled down to seven basic insights:

1. Be aware of hidden processes! The most important insight is to be aware that any primary sensory or emotional stimulus, whether pleasurable or unpleasant, will give rise to opponent processes of an contrasting nature.  Even though you most likely cannot directly perceive them, these opponent processes are happening–and even growing in strength–at the very same time as the primary emotions and sensations that you do perceive.  When the primary emotions and sensations stop or pause, these contrasting processes emerge into consciousness!  For example if you put your hand in cold water, a “warm” opponent processes is being stimulated, but you feel that warmth only once you withdraw your hand from the water. And the pleasure of overindulging in sweet desserts is likely to be followed by an unpleasant reaction that arises some time after you stop eating.
2. Avoid overexposure to pleasurable stimuli. This does not mean that you should minimize or avoid direct pleasure! Just be aware that too much of a good thing too often can backfire — and be aware WHY that is so. By remaining vigilant, you need only to moderate the intensity and frequency of pleasant stimuli to ensure that the opponent processes do not build up. For example, eating small portions of delicious foods, and spacing out meals — or even individual bites — will tend to reduce the level the opponent processes (cravings) that would otherwise reinforce appetite and cravings. When you go for that second cup of coffee, you may marginally increase your alertness in the short term, but realize that you are at the same time continuing to stimulate a reactive opponent process, counteracting the caffeine high, that may lead to increased tiredness later on.  There is a biological argument for moderation!
3. Use unpleasant and stressful stimuli to indirectly build pleasure. This is one of the most powerful insights of the opponent-process theory. By judiciously exposing ourselves to intermittent stresses, of sufficient intensity and frequency, we activate in our bodies and psyches some powerful opponent processes, which in turn result in heightened pleasure and satisfaction. Depending on the type of stimulus, these indirect pleasures can be short-lived or more sustained. Stressful or unpleasant stimuli can therefore be thought of as a form of “psychological hormesis”:  The nervous systems is activating certain pleasurable inhibitory processes in order to defend against and build tolerance to stress. These pleasure-generating defense mechanisms are real, biological processes which operate in our nervous systems. One well known example is the production of endorphins, our natural opiates, which can be produced by engaging in strenuous exercise. Endorphins literally help us to endure the pain of exercise by providing a counteracting pleasure. So by increasing the intensity and frequency of stress exposures, we are not just building tolerance–we are actively building up a sustained background “tone” of pleasurable emotions. This is very much in line with what the Stoics called “tranquility”. As explained on the Stoicism page, Stoic tranquility is not apathy or a lack of feeling!  On the contrary, it is a positive sense of equanimity, contentment, and happiness that endures and supports us.  It is the opposite of depression; you might even call it “elevation”.
4. Indirect pleasure is superior to direct pleasure. So we have learned that we can paradoxically use pain or discomfort to indirectly cause pleasure.  But is there any reason to think that the pleasure resulting from running, hard work, cold showers, or skydiving is superior to the pleasure from sweet desserts or scratching an itch? Aren’t they equivalent? Doesn’t any pleasure, whether direct or indirect, nevertheless have the potential to lead to addiction?  This is an interesting question, but I think the opponent-process theory makes the case that indirect pleasures — those that results as reactions to stress — are superior. There are two main reasons for this:  First, according to Solomon, opponent-processes are “sluggish”; they take time to build, and decay more slowly. They continue even when the stimulus stops. And unlike direct pleasures, which may be more intense, there is no sudden withdrawal reaction when they stop, hence no “craving”. They tend to fade slowly. Second, the initial unpleasant stimulus — exercise, work, cold sensations — must be sufficiently unpleasant to be effective. This initial unpleasantness will always be a “barrier” that requires conscious effort to face and overcome. If it starts to become “addictive”, it is easier to let this unpleasant barrier stand in the way. It is easy to decide not to go running or take a cold shower if one becomes concerned it is becoming too habit-forming or detrimental to one’s health.
5. Use unpleasant stimuli to counteract addictive pleasures. This is one of the most interesting, and I think unexplored, applications of the opponent-process theory. Addictions are characterized by increased cravings. These arise when opponent process build up in reaction to pleasurable primary stimuli that are too intense and frequent. The craving can become a sustained background “tone” that is always there when the pleasurable stimulus is absent. And the “savings” effect makes the opponent cravings come back more easily. But we can overpower these cravings by deliberately introducing unpleasant stimuli at the same time as the addictive cravings, in order to generate new pleasurable opponent processes. The key is to time the unpleasant stimuli to coincide with cravings or withdrawal, and make them sufficiently intense and frequent, that one builds up sufficient background pleasure tone to counteract the unpleasant anxiety that typically accompanies addictions. So fight cravings by adding a new stressful activity like high intensity exercise, cold showers, or intermittent fasting! It may also help explain why cue exposure therapy — exposing oneself to the forbidden fruit without partaking — can often be more effective in extinguishing addictions than merely abstaining or avoiding the addictive stimulus. It is possible that active cue exposure might generate a type of acute “stress” that “burns out “the original craving with an opposing pleasure. This is like fighting fire with fire!
6. Don’t abuse pain and stress. Despite the potential benefits of controlled stress and unpleasant stimuli to indirectly induce sustained pleasure or “elevation”, this approach is easy to misinterpret or apply incorrectly. Some might take this to be a justification for masochism or self-harm, but it is not. The key here is to carefully think through the consequences of one’s actions. Does the application of the stress or unpleasantness result in an objective strengthening of your body and mind — or does it lead to physical or psychological harm?  Depressed teens sometimes engage in a practice called “cutting” to relieve their depression and apathy, because it can actually reactivate pleasure or a rush that fills a gap and can become addictive. Most likely, this pleasure can be explained in terms of opponent processes that release some of the same endorphins or other neurotransmitters as exercise does. But one needs to distinguish between objectively harmful activities like cutting and beneficial habits like exercise or cold showers. Far from injuring oneself, these beneficial uses of stress and “pain” act to act to build strength, resilience, and long-term happiness.
7. Optimize your stimulation schedule. Be aware of critical decay durations and savings effects of opponent processes, for both pleasant and unpleasant stimuli. Addictions and cravings can be minimized by reducing the frequency of exposure to pleasure-triggers to allow enough time for any cravings to decay. The next time you are mindlessly wolfing down bite after bite of an addictive snack like popcorn or candy, try spacing out bites to allow the craving sensations to die off between bites and see whether you end up satisfied with fewer bites. On the flip side, if you are finding it hard to get started on a healthy habit like strenuous exercise, cold showers, or fasting, it may be that you need to increase the frequency and intensity of the new habit until it takes. According to Solomon, it will become increasingly pleasant if you do this.

Since becoming aware of the opponent-process theory, I applied it to myself in two instances recently:

• On the pleasure side, I reduced my craving for alcohol by drinking less frequently, and limiting the amount that I drink.   The pleasure remains, but the daily cravings have disappeared. I’ve documented this on the Discussion Forum of this blog.
• On the pain side, I have increased my enjoyment of cold showers by never missing a day, by lengthening the showers, and by making sure to expose my most sensitive body parts to the coldness.  This has significantly increased the pleasure I feel, and it comes on more quickly while in the shower (within 10-15 seconds, versus previously more than a minute) and the warm, exhilarating post-shower feeling lasts all morning.  I’m happy all the time, and I definitely feel less stress.

Think about how this might apply to your own situation. Are there pleasures in your life that tend to result in cravings when they are absent? Can you think of ways to introduce healthful but somewhat unpleasant stress into your life in a way that builds your resilience and at the same time a deeper level of satisfaction and sustained pleasure?  Can you use this indirect pleasure to displace cravings or dissatisfaction? And in both cases, how aware are you of the relationship between the intensity and frequency of the stimuli, and the tendency to foster opposing processes that turn pleasures into pains, and pains into pleasures?

The potential applications are infinite!

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!