Change your receptors, change your set point

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 receptor levels in alcoholics, cocaine addicts, and addicted smokers.  And, as you might guess, the same pattern of reduced levels of dopamine receptors was observed in addicts vs. non-addicted controls.  This is illustrated in the PET scan to the right, which shows dopamine binding activity for addicts (top row) vs. non-addicts (bottom row). Regions of greatest dopamine receptor activity are indicated with a color scale starting from red (most active), descending through yellow and green to blue and purple (least active).

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

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

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

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

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

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

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


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

Step 1:  Strenuous exercise. Regular, intense exercise can upregulate your insulin receptors. In Dr. Bernstein’s Diabetes 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”.


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.


  1. Amanda

    This is so insightful. I never realized that being overweight had so much in common with addiction and depression. But there it is in the dopamine receptor brain scans. I always bought into the set point idea based on what I’ve read, but now I’m having my doubts. I’ve tried working out in the gym on treadmill, but it just makes me hungry. Maybe I need to get started with weights and intermittent fasting, if that will really grow new insulin and dopamine receptors. You’ve given me some hope and reason to try this. Thanks!

  2. In this week I experienced some problems that less can I face so I had a little stress or depression. After I read your article was nothing to do with what I experienced today and become a little solutions to solve my problem. Immediately, if my nerves could be disrupted by neurotransmitters can not solve my problem? Neurotransmitters How can I stay awake? Please explanations and thanks.

    • Todd

      AnDg, I’m not quite sure what you are asking. Is the problem depression or is it fatigue? There is evidence that you energy level and sense of pleasure can be increased by engaging in intense, strenuous exercise, cutting back on sugar and starch, intermittent fasting and cold showers. Check out the other pages and posts on this blog for more information on these practices. If you are having trouble staying awake, I would suggest getting more sleep and avoiding coffee, caffeinated and sweetened beverages, starches and sweet fruits. You may experience extra fatigue and tiredness for several days, but then you’ll start to regain energy.

  3. Tim Amann


    First of all, thank you for your incredible website. As someone who is not at all formally trained in biology/neuroscience, but somewhat of an armchair, I have been looking for this type of information and analysis for considerable time and without success until today.

    I have wondered about downregulation for a long time as it seemed that any attempt to increase serotonin/dopamine/norepinephrine is accompanied by downregultion in the medium and long-term, resulting, at best in a zero-sum gain. You mentioned a dopamine blocker to help alcoholic addiction, which reminded me of a question I’ve had. If neurotransmitter agonists and reuptake inhibitors cause downregulation, could antagonists (or anything else that could decrease NE/DA/SE) be used to fast-track upregulation? Could use of these chemicals on an intermittent basis be effective to reestablish receptor sensitivity?

    Also in relation to serotonin/appetite, what’s your take on aspartame? I’m a huge drinker of diet soda (~4 to 6 liters/day) and have been battling a weight problem (~30% bodyfat) with a constant appetite almost regardless of consumption. From what I have read, aspartame doesn’t have an effect on insulin. If that is correct, I am curious about your take on two other possible pathways. One theory I’ve heard that the taste without caloric value could eventually cause dysfunction in the brain relative to its ability to recognize calories (foods with calories would not be recognized as such and cause overeating). The other possibility is that because aspartame contains 50% phenylalanine, and from what I have heard phenylalanine competes with tryptophan, it reduces serotonin production, increasing appetite, especially with the amount and frequency I drink diet soda. Now that I think of it, the constant exposure to caffeine supposedly reduces serotonin in the long-run as well.

    Any thoughts you had would be appreciated. Thank you.

    • Todd


      Your suggestion of a neurotransmitter antagonist to reestablish receptor sensitivity is quite logical. In fact, you can argue that that is what naltrexone is doing for alcoholics. So one could take the next step and develop “pro-depressants” that would temporarily suppress dopamine or serotinin but lead to a beneficial long term upregulation of the receptors.

      There are a number of problem with pharmaceuticals for modulating receptor activity, however. The biggest issue is that neurotransmitter levels are hard to control or dial in. If problems arise, you may be unable to quickly or easily correct the situation, so this could be dangerous.

      That’s why I think the best approach to upregulating receptors is to use “real world stressors”: intermittent intense challenges, like exercise, cold showers, dietary restrictions, and the like. These are easy to control and modulate up or down as needed. I also think that changing our reactions and behavior is not as simple as turning up or down the sheer number of receptors. Perceptions and behaviors occur in the context of complex neural circuits, which are arranged spatiotemporally in the brain. So it is likely that learning from real world stressors induces differential changes in receptor sensitivity along circuits. That is why I think that administering antidepressants or other “bulk” neurotransmitter modulators cannot possibly be as effective as experiential interventions, including psychotherapy or, better yet, real world challenges. I have no absolute proof for this, it’s just my considered opinion based on a lot of reading and my personal observations.

      Regarding diet sodas, there is some debate about whether aspartame leads to weight gain and appetite. See for example this balanced review:

      I do think there is plenty of evidence that artificial sweeteners can increase appetite by means of psychologically conditioning the cephalic phase insulin response. But whether I’m right or not, why not do a simple experiment on yourself? Go cold turkey for 3 or 4 days and see what happens. Drink no regular sodas or diet sodas, or even any sweet fruit juices. Of course, you’ll have to substitute something. I’d suggest water, unsweetened flavored teas (there are many good orange, apple or other flavored teas), or you could try vegetable juices like V-8. Prediction: You’ll find the first 2 days very hard, and you may feel cravings, tiredness or crankiness. You may even feel bored. (I think you understand why). When you get these feelings, try substituting something physically challenging (walking or exercise) or substitute something else relaxing or pleasureable that doesn’t involve food. But my guess is that after 3 or 4 days, you’ll see a marked improvement in mood, a reduced appetite, and perhaps a path to weight loss.

      Try it and see what happens. And let us know.

      • Tim Amann


        Thanks for the great information. I can see how using pharmaceuticals to upregulate receptors could be risky, and using real world stressors could be more effective. I’ve attempted numerous times to use pharmaceuticals and high dosing various supplements to change urges/behavior/physiology without much success (outside of smart diet and exercise). I’ve have already started to implement IF, cold showers and have restarted my weight training and low carb diet.

        With all this, I think I will hold off on the cutting out diet soda for a bit as it I think the IF+low carb and cutting of diet soda would be too much in the short term, at least during the fasting portion of the day. Being that it seems I use diet soda in part to suppress my appetite in the short-term (dopamine and serotonin?), I think it may be logical to assume it probably causes an appetite increase in the long-term (receptor downregulation?). Once I get a bit more comfortable with the fasting, hopefully over the next couple weeks, I’ll quickly taper the diet soda intake to zero. If I see any positive changes post the craving period, I’ll be sure to report. Thanks again.

        • Todd

          Sounds like a wise approach, Tim. It’s always best to do things gradually and see how it goes. You’ve already started making some substantial changes!

  4. Tim Amann


    I think a relevant aside is the potential negative impact antioxidants have on exercise induced changes in insulin sensitivity:

    If the study holds true, I think it begs the question on when the appropriate time to consume antioxidants (food, drink or supplement form) is relative to training. I believe the prevailing viewpoint is that antioxidants have a positive impact on insulin sensitivity. If that is indeed generally correct, they may may need to consumed in a specific window not to interfere with training induced insulin sensitivity adaptations.

    Any thoughts on that? If this study holds true, I would think you would want to take them early enough so they they are not in your system in relevant amounts during training and would need to be consumed after free radicals have had enough time to induce the sensitizing proteins.

    • Todd


      Thanks for the link. Coincidentally, I just completed a new post that echos the point the article makes about antioxidants inhibiting the beneficial adaptive effects of exercise. It think it may also help address your question about when to consume antioxidant foods or supplements. You may be surprised at the answer I give in the new post — which is basically to avoid taking any foods or supplements for their specific antioxidant content. I’d be interested in your reaction.


  5. Sometimes, I feel depressed but after I read your post I learn something useful. Al least I know how to control my depressed feeling.

  6. Doc

    Depression isn’t generally considered the result of downregulation of 5HT receptors, but of upregulation.

    • Todd


      People used to believe what you said. But a decade ago, PET scan studies revealed that depression is associated with a reduced number of serotonin (5HT) receptors. For example, studies by Mintun and Mathis at the University of Pittsburgh demonstrated this.

      Because most people with depression get better when their serotonin levels increase after treatment with SSRIs, Mintun initially believed the PET scans would reveal high levels of serotonin receptors in brain structures linked to depression. The hypothesis was that because less serotonin was available, the brain would try to compensate by making more receptors. But that’s not what the researchers found. In the February issue of the journal Biological Psychiatry, Mintun and his colleagues reported that the depressed people actually had fewer serotonin receptors throughout the brain and significantly fewer receptors in a key structure called the hippocampus, an area that acts as a gateway between memory and mood, among other processes.

      Do you have any data or references that would contradict this?


  7. Steve

    Hi,I found your website yesterday and I must say there is some great stuff on here.

    Just a quick question, If dopamine is up-regulated via exercise and intermittent fasting what is the deal with exercise addicts and anorexics/bulimics?

    Also natrexone works because it acts like a endorphin re-uptake inhibitor tricking the body to making more endorphins but only at super low doses.

    Inhibitors combined with amino acid preloading and good nutrition are thee best way to up-regulate receptors in my experience.

    • Todd


      The best theory of addiction I’ve found is the one described in my post on the opponent-process theory of emotion. I think there are two types of “addiction”. The more insidious is addiction to direct pleasures such as drugs, food, sex and video games, because it involves a tolerance effect whereby dopamine is progressively ramped up, while sensitivity to dopamine is ramped down. This leaves one feeling awful between exposures. The second type is addiction to indirect pleasures, what you might call “second-order” addiction. The pleasure in exercising, thrills like skydiving, and strenuous challenges — or even cold showers — involves a relatively brief unpleasant initial phase, followed by a longer, more extended aftermath of pleasure. Typically the pleasure extends for a long time between the brief exposures. It is more of a feeling of general well-being than a dopamine spike. Generally, these second-order addictions make your life better and you feel better more of the time. Your receptors are unregulated and you become more sensitive to pleasure and more joyful. And the brief unpleasant exposures become more tolerable. I suppose that an exercise addiction can itself get out of control if pursued too intently, but it is far less damaging that a drug addiction.

      I would not place anoxeria and bulimia in the same category as exercise addiction. Eating disorders involve serious dysfunction and disregulation of the pleasure system. Often the result is anhedonia, the inability to experience pleasure. The perception of body image becomes seriously distorted. Low dose naltrexone does appear to be an effective way to up-regulate dopamine and endorphin receptors by temporarily “starving” them. Your point about amino acid preloading is interesting in this context. I’d love to learn more about it.

      Thanks for the good comments.


  8. Eric

    Great article, thank you! And two thousands years ago Epictetus says:

    “Be content to practice the life of an invalid, that you may one day live the life of a healthy man.”

  9. Michael Loubier

    I just wanted to say thank you. I’ve been struggling with weight for years, the biggest problem being that I didn’t want to admit to myself that I had a problem with my weight. Once I admitted that, I entered into a mild but repetitive series of depression-like symptoms, which eventually brought about a diagnosis of narcolepsy (mild) and stress, which has since caused my insides, for lack of a better word, to cause me constant discomfort and pain. I read this blog and watched your lecture on IF just a few days ago, and I’m already noticing an improvement. My normal diet consists of several cans of soda a day, and a few glasses at work, amounting probably to at least 2 liters a day, as well as a constant cycle of over-eating. My problem with over-eating has always been, and still is, that I do not get a full feeling until well after I have finished eating. Using IF, I am regulating this feeling, though unsuccessfully at first, and controlling my body instead of letting it control me. I don’t currently have access to a gym, but I’ve been trying to run while hungry (as talked about in your IF videos) to promote those receptors. I’ve since switched from 3-5 meals a day to 2, and I now tend towards 1 caffeinated beverage (can usually) a day, supplementing previous cravings with flavored water. I’m getting a little long-winded here, so I’ll get on with my question. I was wondering if you had a list or chart of some kind of what activities promoted which receptors. I’m having a hard time going through all of your articles to gather all of the information, and I suppose I’ve probably tried to read too much too fast. I was thinking just a chart of some kind with the receptors, their properties, and what activities (IF, anaerobic exercise, cold showers…etc) would promote them. Especially one using, say, Google Docs that people can comment on their success with different methods. Any chance of something like this happening?

    • Todd

      Hi Michael,

      In addition to starting IF, cutting out the sodas was an excellent move on your part.

      Regarding receptors, I wish it were a simple matter to associate specific receptor types with specific activities or stimuli like diet or exercise. The most important of these are the G-coupled protein receptors on the surfaces of many cells. The brain, nervous system, digestive system, muscular system and immune system are replete with a wide variety of receptors to various neuropeptides, hormones, energy molecules and other signaling compounds that act as both activators and inhibitors, often in a synergistic manner. This is a very complex system, and we are only beginning to map it out. So a chart as you are suggesting would be wonderful…but doesn’t exist yet.

      What I’ve tried to do in my blog is only to highlight some general principles that are becoming evident. The most important of these principles is that of homeostasis: The body tries to maintain a constant level of key neurotransmitters such as dopamine, serotonin and acetylcholine, and energy molecules like glucose and fat. If you reduce the input stimulus, the body grows more receptors to compensate and provide more signal. So by challenging yourself with fasting, intense exercise, cold exposure, etc., your body will compensate in the opposite direction. If you do this frequently, the signal compensation will be sustained. Take a look at my post on the Opponent process theory of emotion for an elaboration of this framework.


  10. Mark

    I think there is better information here than so many of the books I have read. I have what I think is low dopamine. I am not depressed, I usually dont feel bad at all, but interest in things is so low. I have shaky legs and I love chocololate. I have been finding also as you have said that there is no quick fix, it’s rebuilding up the functioning of neurotransmitters. I always thought I had low this or that, I take tyrosine often, but I never quite thought of the issue being the receptors. I am just trying to get better and this information here is great. Thanks.

  11. Sue

    Hi Todd,

    I just ran across your site- it’s very nice to read such a thoughtful and coherent blog!

    I would like to share my experience of set-point in case it might be relevant. I am a weight watchers lifetime member (though not at my ‘target’ weight currently, but I have been at a fairly stable set-point for the last 2 or so years), which is mainly to say that I have lots of experience with dieting, and not dieting, over the past 30-odd years. Currently I am not dieting. I have been just focusing on healthy eating and am toying with the idea of dieting again to reduce weight stress on some damaged joints.

    Back in the mid-80s I read a book on changing your weight set-point (can’t recall the title), which, of all that I have ever read on dieting philosophy, most accurately described my subsequent direct experiences. The takeaway from that book was that set-points are changeable, and that exercise is required.

    Basically, I have experienced the dieting and (sometimes delayed) weight regain multiple times, but I have also spent quite a few consecutive years at each of these weight set-points: 132, 155, 172, and 180 (not in chronological order, and sometimes more than once at the same weight).

    Although I have eventually come to appreciate how much better I feel with good insulin sensitivity, and follow a generally low-carb eating pattern at the moment, it has taken a long time to get there. Point is, that in the past, regardless of these setpoints, I was often in a “bad place” with respect to carb consumption and blood sugar, though not understanding it at the time, but it didn’t seem to have affected the setpoint maintenance mechanism much, at least once I was at a set-point. While at these setpoints, other than watching out for prolonged ‘accidental’ overeating (like extended holiday seasons), I generally have not paid a lot of attention to what I ate or did not eat.

    The one possibly helpful observation that I can offer is that establishing a new setpoint (for me) has, strictly without exception, involved two factors:

    1) regular, moderately intense exercise approaching and during the period of ‘establishment’ (but not necessarily afterwards), and

    2) regimented caloric control at a level adequate for maintaining the new weight, for AT LEAST six weeks and preferably 3+ months. To me, this has meant absolutely no “cheat” days and no deprivation days- I had to eat an adequate number of calories to maintain the weight each and every day. If I ate too many or too few calories even one or two days during that time, a rebound within the next several months was inevitable.

    Leaving the “setpoint oasis” has usually been triggered by an intense stressor: major surgery which triggered a 20-lb weight loss, followed by a rebound gain; severe and prolonged emotional stress, etc.

    So that is my experience, and I hope that it may be a bit of useful input for you. And again, I’m really enjoying reading your site, thanks!

    • Todd


      Thanks for your thoughtful post. In reply, I have a few questions/comments for you:
      1. Can you can dig up the title or author of the 1980s book you read about changeable set points? I’d be most interested.
      2. It’s very interesting that you have had such precise, but amply spaced, set points. These are almost like “nodes” or stable sticking points. I found similar “plateaus” in my weight loss. In my other post on “How to break through a plateau“, I posited that the stability of these set points arises from discrete changes in dietary and exercise habits. I compared moving from one set point to another with the analogy of crossing a steam by jumping from one stable boulder to the next. Time on set point plateaus is useful in gathering energy and confidence to “jump” to the next plateau. I’m interested to know whether this way of looking at things resonates with your experience.
      3. You are quite correct that regaining insulin sensitivity is a slow process that requires patience and discipline. But at the end of the journey it’s worth it.
      4. I think you are right that exercise is a particularly important success factor in breaking through plateaus. You suggest that it is important mainly in the transitions to establish new set points, but not necessarily afterwards. I’m not sure I understand that. I’ve found that to maintain a new set point, I have to maintain the “upgraded” exercise habit.
      5. Your point about regimented calorie control is interesting. I must admit I’m not much of a calorie counter. I agree that calories are important, but I find it more useful to focus on what foods and eating patterns influence my appetite, and the calories tend to take care of themselves.
      6. Perhaps your most interesting observation is that even a single deviation or “cheat” from your plan (or conversely too much deprivation) triggered a rebound within a period of a few months. I don’t think I’ve experienced this myself, but perhaps I’ve not paid close enough attention. Perhaps you could expand on this point by describing a specific example and speculating about the physiological or psychological reasons that account for this. Can it be related to changes in insulin sentivity or brain receptors?
      7. You and I agree that stress is a major factor in weight control — but chronic stress in particular, because it dysregulates cortisol. I’ve found that — perhaps paradoxically — the best way to combat chronic stress is to voluntarily ADD acute stress. And the most useful acute stress is intense but brief exercise. It seems to almost inoculate you from the negative effects of chronic stress. This is something that is so obvious when you do it regularly, but so hard to get started with if you are in the middle of a stressful period and have been lax in exercise. People who are stuck in a non-exercise habit can find it difficult to believe that hard exercise will dig them out of it.

      Glad you are enjoying the blog!


  12. Toni

    I don’t really know what this article means but I found it prior to finding your information on leptin and dopamine…. it discusses dopamine and anorexia.

    I started Jack Kruse’s Leptin Reset at the beginning of the year and I felt great! I did give it up but reading your blog post has made it seem more clear to me that I need to get back to it.


  13. Michael Johnson

    This is true, I’ve known this for a couple years now. It actually pisses me off when all I ever hear as a natural solution to depression or appetite problems is to take tyrosine or 5-htp, or any problem, here, they say, take this acetlycholine supplemt, this will INCREASE your GABA, this will INCREASE your whatever. That is such an ignorant one-track way of looking at it. It is way more complicated than that and it baffles my mind how many people think this. That book called “the edge effect” was written only from the viewpoint that the problem is defieciency and having desperately been searching for a cure of a conditon from Hell itself, hearing this all the time drives me nuts. I have a full blown, stubborn case of Anhedonia that responds to nothing, including modern treatment of drugs and many, many alternative treatments including energy/quantum physics healing therapies, counseling, and many others. Also have an eating disorder, ocd, ptsd and insomia. The first day I ever took 5-htp I had a normal appetite for the first time ever in my entire life and felt a strange sense of calmness, or like I just felt more “together” (though the dead feeling from the Anhedonia was still there). It lasted only a day and a half, even though I kept taking the pills. My entire life, the **Only** thing that ever made me feel good, was fasting. When I ate, my whole life would go downhill, but when I stopped eating my pleasure and motivation increased 100%. The thing is, I was never able to sustain that. Inevitably I would always end up going on a binge sooner or later and 3-24 months of depression and low motivation would follow. And, when I stopped eating my ocd and ptsd and insomnia got much worse, at the same time my pleasure and motivation issues got better. So it was one or the other, my choice was either live in this hell or live in that hell. So in a way this receptor theory is true and in a way it’s not – if I am fasting and feeling much more pleasure, there had to be something wrong with this system that always brought me back to square one. If I am exercising and eating right and doing the work, why did I always fall right back down? And what do you do if your receptors are completely 100% gone or desensitized, as in the case of Anhedonia? What do you do when you have two different disorders, one like ocd and insomia, that is helped by eating, and another like an Anhedonic-type depression that is worsened by eating, on top of an eating disorder where you can’t stop eating in the first place??

    • Todd


      Thanks for posting your story and your experiences. I’m not a trained psychotherapist, so take whatever suggestions I make as just that — suggestions to try. I think your experience with fasting is a key benchmark, since the effect has been so dramatic for you. The key with “fasting” is to turn it into a sustainable pattern. This is what intermittent fasting is all about. Try to set up a pattern that works for you — where you avoid food for 16-20 hours a day and eat within a defined 4-8 hour window. Experiment with the timing and length of the eating window — it could be in the middle of the day, or maybe around dinner time. But be consistent. If you establish a pattern and know when you will eat each day, you will relax and forget about food while fasting and look forward to the enhanced taste of food during your eating window. Most people experience initially eating somewhat more during the eating window, but then this settles down to a reduced amount of food. People generally find that the patterned eating does not lead to bingeing.

      For more information, you can check out the free e-book and forum at

      To combat anhedonia, have you considered adding brief, but intense exercise or cold showers into your routine? Perhaps it sounds dreadful, but I have found that those two additions to my life have done more than any other practice to increase overall pleasure. Check out these two posts:

      Good luck — and let me know if any of this helps!


  14. Michael Johnson

    I have eaten only once a day in the morning for many years now (intermittent fasting), or I’ve tried to and been succesful most of the time. Still, even doing that, I always ended up back in the binge depression cycle. So even though my receptors were up to where they should be, there was that something something…something… that made sure they always came back down. Then the Anhedonia came full force and now nothing helps, not fasting not anything. I tried intense exercise, nothing, hydrotherapy, nothing. I will check out those links, thank you for those. You’ve presented some brilliant ideas and this is the best theory I’ve ever heard but there’s still something missing…

    • Todd


      I appreciate hearing about your experiences with anhedonia. I’d like to know more about how you experience it — is a complete flatness or lack of pleasure? Or are there any ups and downs?

      I’m sorry to hear that nothing you have tried is working. I’ll be the first to acknowledge that my “theory” is only an preliminary attempt to make sense of the research I’ve read. It is not surprising that there may be “something missing” in the explanation. I would very much be interested in what you think that “something missing” might be.



  15. Michael Johnson

    Anhedonia is like youre alive, but you feel halfway dead. It is actually painful in a very real way, but it’s not a pain that’s easy to describe, I guess you could say it’s a spiritual pain, like you’re suffocating somewhere that you can’t quite put your finger on. Let me put it this way: Anhedonia is the opposite of mindfulness. That is what they mean when anhedonics say they lose track of time – you can sit on your couch for years and years and lose track of time because there is no mindfulness. It feels like you’re halfway unconscious. I’ve heard others with it say they don’t have any emotions, or they can’t feel positive emotions but that isn’t exactly true – what is going on is that they can’t Enjoy their positive emotions. That’s why people with Anhedonia still laugh and smile, as opposed to a suicidal person who you would never see even begin to crack a smile. We feel “excited” or “optimistic” but the dead feeling won’t allow you to feel the pleasure of that emotion. So it might as well not be there at all. At least then people wouldn’t treat us like like we’re making it up or faking something. You can feel good but not enjoy it – who would of thought? I’ve talked to both a Buddhist monk and a Dianetics auditor and they both told me to try to think of something that would be worse than anhedonia and that would help. The only thing I can come up with is torture.

    • Todd


      Thanks for your explanation. I see now that anhedonia is not a simple lack of pleasure, but an inability to experience pleasure (or pain for that matter) with full engagement and mindfulness. What I have read about anhedonia suggests that it does involve an impairment to the brain’s reward system, in particular the dopamine system. Dopamine is associated not only with pleasure but with “salience” — the ability of the brain to attach conscious significance and importance to experiences.

      A shortage of dopamine (or a shortage of sensitive dopamine receptors) can very well be a likely cause of anhedonia, at least in some cases.

      This brings us back to the point of your original question: Is there any way to upregulate or resensitize dopamine receptors in someone with an impaired dopamine repair system? Given that that the D2 dopamine receptor is a G-coupled protein receptor, I would expect it to upregulate in the same way that other G-coupled protein receptors do — namely, to increase and desensitize in response to deprivation. As hard as it may seem, the only way to truly effect this is to subject yourself to unpleasant and physically difficult situations repeatedly and over extended timeframes.

      What this means is activities such as fasting, cold showers, and sprinting — to the point that they are truly unpleasant, and at the limit of what you can tolerate. One should be careful not to cross over into physical pain. There is a fine line between challenge or exertion and pain. But it must be repeated frequently over a period of many weeks to really stimulate any neurogenesis. The brain is plastic, but it changes quite slowly.

      Again, I’m not a clinician, so I offer you these suggestions only from the perspective of biological theory. I’ve not experienced anhedonia, but I have experienced the opposite — a significant increase in my own sense of mindfulness and generalized pleasure as a consequence of engaging in very difficult physical challenges such as the ones I mentioned.

      Good luck,


    • Brentg

      I really enjoyed your comments, and thank you for them. I know this is an older comment, but everything you said mirrors my life. It seems that Todd is close here, but yea something is missing. I took benzodiazepines for 15 year, talk about down regulation and anhedonia. About the monks and torture, yea thats cold showers, sprinting for me. Although I enjoy intermittent fasting. Have you figured anything else out in the last year, I am desperate to know what you have found out. Thanks for your comments.


  16. Spectacular article. Thank you very much.

    In addition to receptor modification, fasted anaerobic exercise has also been shown to favorably modify gene expression. An article on the mTOR pathway would be a great follow up to this article.

  17. gavrilo

    Hi Todd!

    Great article. Kepp up the good work.

    You recommend strenuous and anaerobic exercise. Right away I think of interval training.

    There are numerous IT protocols (i.e. tabata, peak eight, etc.).

    Please suggest a minimal IT protocol to upregulate my receptors, including number of sprints per session, rest periods between sprints and sessions per week. I’m assuming all out effort per sprint.


    • Todd


      I’m not an exercise physiologist or trainer myself, so I can’t recommend a specific protocol. All I do is try to interpret the science, and the research in animals shows the benefit of almost any intense exercise in receptor upregulation. I personally do interval sprints, some weights and — my favorite — rock climbing involving some hairy overhangs that get the heart pumping and the arms pumped. But your suggestion of Tabata and other interval training protocols sounds right to me. You’ll find many exercise sites that can provide details on this. My suggestion is to experiment and see what works for you. The key is to alternate between pushing yourself hard, and allowing enough time for rest, recovery and regeneration.


  18. Alex

    Hi, Todd. This is a small nitpick, but I believe this comment is partially untrue:

    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.

    The brain and liver take up glucose via other mechanisms that are not insulin-dependent, so I believe brain and liver should not be included in this list of tissues that require insulin for blood glucose takeup.

    Great article!


    • Todd


      Thanks for chiming in here. You are of course right that there are non-insulin dependent mechanisms of glucose uptake — not just in brain and liver, but also in other tissues. Yet that does not obviate the fact that there is also an insulin-mediated mechanism in the brain and liver and it is significant. Otherwise, how do you explain insulin resistance in the brain and liver? These are well recognized phenomena, thought to contribute to conditions such as Alzheimer’s and fatty liver disease (hepatic steatosis):


  19. Yaro

    Hey Todd, I just read your article and I’d like to add my thoughts to this (great, great article by the way)…

    If you take your article and you keep rewinding it back and try to reach the ultimate source of change you will find yourself in a persons subconscious. The change in your body will come once you stop thinking as an overweight individual trying to get in shape and lose weight, but as an athletic, fit person who gained a bunch of weight over night and now you need to find a way to go back to your former self. I think the frame of mind in people is very important. Most “skinny” people in my life always complain when they gain several pounds or look a bit pudgy in the mirro. Most chubby/fat people in my life always complain that it’s hard to lose weight, get in shape, get some exercise into their daily lives. I believe the skinny/fit person has a completely different mind set and starting point on how they view themselves vs the fat/overweight person.

    If you can convince people to think that they are fit, thin and athletic, then they will start thinking that their weight gain is a temporary speed bump and they wil try everything within their power to get back to their old self. As long as the fat/overweight person doesn’t accept his body as truly his/hers then change can happen. I also think this is how some fit/skinny people gain lots of weight over the years and stay overweight later in life. They just accept their bodies as the months/years/decades go by! By accepting that bodytype in their mind, they solidify their self image and things continue to spiral out of control ever so slowly. Excercise is lessened, eating a lot increases, leptin resistance goes down, the “pleasure” senses go down, thus requiring more pleasure in their lives to achieve homeostasis. What do you think of what I said?

  20. Todd, I just spent hours this evening reading about different ways to increase neurotransmitters since I am struggling with balance these last few years, and finally convinced myself it wasn’t “just my personality”.

    Anyhow I just wanted to say I really appreciate your article since it is seeing it from the other way round, and I am going to think a lot more about increasing receptor sensitivity versus increasing the their load. I have been eating the Jaminet’s Perfect Health Diet for about two years now which has certainly put me in good standing.

    Unfortunately in my twenties I took MDMA (3,4-methylenedioxy-N-methylamphetamine) over a space of two years (likely < 20 pills in total) which probably did me no good. The cause of my mood swings and "personality" ten years later, who knows?

    Thanks again though, a very refreshing read.

    • Todd


      You’re welcome. I think the focus on transient neurotransmitters — rather than on receptors — has led many people astray. MDMA (Ecstasy) can impair receptor sensitivity:

      I think you’ll find that natural stressors like exercise, cold exposure, and food restriction are among the most effective ways to restore receptor sensitivity in the brain.


  21. Kitsune

    Thank you, Todd, for this wonderful article. It goes far beyond the usual simplistic solutions to the problems of obesity, depression and addiction — I just wish we could be seeing more information like this in the mainstream media.

    I have one question for you, for which I was Googling when I stumbled across this website. I have been a sugar addict all my life and for the past several years have been trying unsuccessfully to stick to the Paleolithic Diet, combining it with exercise as much as I can. I am in my fourth week of being ‘on the trolley’ again now after months of quite bad sugar/carb bingeing but feel worse rather than better; it’s very hard to cope with and I am wondering how long it is likely to take until various receptors upregulate themselves enough for me to feel like I can get on with a normal life free of cravings, anxiety and other symptoms. I guess I really put my body through some abuse this time, but it’s hard when the cure feels worse than the disease. Might I see some better results in the coming months if I patiently carry on as I am?

    • Todd


      I empathize for your struggle with sugar. I don’t have sugar cravings myself, but I know from others how addictive it can be. You’ll need a long time to decondition — probably at least a month. Try not to focus on what you are missing, but instead try to find other non-sweet foods that give you pleasure, because we all need pleasure in what we eat.

      You may want to read through this thread on the Forum by a sugar addict who goes by the name of “Sugardude”. He experimented with many approaches, but had a hard time of it.

      Like many others, I think he found some help in an herb called gymnema silvestre, which is well known to block sugar cravings:

      You might try that as a temporary aid while you are reconditioning your sugar addiction.

      Good luck,


  22. Alex

    Love the article, it says a lot of what I’ve studied for the last month in an easy to understand format.

    However I’m quite worried, I’m 4 weeks into SSRI treatment (Celexa) for MDD, and may soon be adding Wellbutrin. I’m worried that after my treatment I’ll be worse off, is there a way to upregulate serotonin receptors?

    • Todd

      Hi Alex,

      Glad to hear you enjoyed the article. Withdrawal from SSRIs (serotonin boosters) and and aminoketones (dopamine boosters) can be tricky, particularly for long time users. There are a few websites and forums dedicated to the issues that can arise, with recommendations for tapering the drugs:

      However, four weeks is a very short time, so the risk of any withdrawal effects should be low. What ever else you do, I think it can only help to upregulate your dopamine receptors and serotonins receptors. As I mention in the article, the best ways to do this are intermittent fasting, high intensity exercise, and — my personal favorite — cold showers!

      Cold showers are a powerful antidepressant and if you keep it up for a week, you’ll notice. I get dozens of personal emails from folks who insist it cured their depression and various addictions. The key is to stay in the cold shower a full 5 minutes and expose all your sensitive parts — head, shoulders, arms, hands, etc. The first day is torture, but by the end of the first week, the discomfort is very short and the afterglow and mood uplift last all day.

      Why does it work? Here is the best explanation of what I call “hedonic reversal”, based upon the opponent process theory of emotion:

      Receptor upregulation is the mechanism by which hedonic reversal occurs.

      Good luck!


  23. Robert

    Hi Todd,

    Very interesting theory. I had an interesting conversation with a retired M.D. / Ph. D. about six months ago and he shared some fascinating information with me.

    1) First receptor resistance occurs and then the number of receptors decreases. The idea being is that receptors change and become less functional and this is less of an alteration than complete receptor dysfunction or destruction.

    2) It can take several months to restore receptor function and perhaps four or more months to create new receptors in the case of significant receptor down regulation.

    3) Intense exercise improves insulin receptor function (hence insulin sensitivity) and he theorized that intense exercise would be beneficial for any G-coupled protein receptor.

    Your thoughts? Also, if you have any references on exercise and G-coupled protein receptor up-regulation I would appreciate it.

    Thank you again for your informative theories and taking the time to fully explain them.

  24. Steve

    Hi Todd,

    I’ve come here looking for nutrition for Leptin upregulation, but now I’m interested in nutritional upregulation of everything else.

    I have Parkinson disease and MS in the family, and Aspergers myself with digestion problems, chemical sensitivity, allergies and inflammation (ironically anti-histamines make me swell pins and needles and go numb). After looking up MS for my nephew I realized I had experienced many of the symptoms, but probably not MS as there are a few things with similar symptoms. However, I did have a hospitalisation from a reaction to haloperidol treatment for my Tourrettes syndrome, which was undiagnosed at the time (not recognized back then) that destroys a number of dopamine production cells in the brain. Over the last ten years I saw a massive down turn in testosterone to around one tenth of normal on a bad day, and by the look of it from a low dopamine response. On top of this I had a mono like infection years before, and some strange reoccurring infection that makes me sick and down plays adrenal and liver function, and drives up inflammation, coming with physical ulcers in the mouth and rebula like spots mainly on the upper body and cracking lips. I got chronic fatigue at the time of the mono that with the rest of this, went for a very long time, and exercise is still really difficult to get good enough regularly to do, as is strength and endurance.

    I tried testosterone therapy with limited effect and negative feed back. Once it was determined that it was brain regulation and the dopamine was linked to it, I tried Mucuna Bean, that is used for Parkinson because of ldopa content and better than ldopa by itself due to other cofactors. After three days I would find that my condition greatly improved as far as dopamine related symptoms for up to 2 weeks without taking another dose. However, this did not always work, and sometimes is ineffectual, now it seems worse, and it seems to depend on something else going on. I did try mild SSRI’s for 6 weeks but declined rapidly falling over etc, shaking, uncontrollable movements and it turns out everything on the list of negative side effects. The interesting thing is that this brought out a lot of the ussually problems including shuffling around slowly, and I will even react to tryptophan. I do not know which is affecting my hormones, and if receptor or hormone level.

    I have low stomach acid (likely related to testosterone and dopamine) and low probiotics, so have resorted to easy to absorb nutrients to boost testosterone and dopamine production, that has greatly increased things (as well as myline repair nutrients, that over lap, and am treating digestion, inflammation, allergy, and apt production) which made my health a lot better more often and a hundred times better when good, out of a thousand times (compared to being bed ridden or unable to lift a tenth my weight). But then I tried Jack 3D (has an adrenal boosting factor) with Macuna etc and it was fantastic for several hours lots of strength and endurance as long as I was not sick from other conditions), day by day, but eventually it wore off and I’ve been weak for a year.

    I have a weight and spine problem too.

    So, exercise is not a consistently reliable option for upregulation, but I am also interested in supplementing with nutrients to achieve what I can. If you could advise me or direct me to information on nutrient’s for upregulation, and what you think of my hormone/receptor situation, that would be most appreciated?

    • M.R.

      You sound a lot like me.

    • Todd


      Your situation is certainly complex, to put it mildly. Even if I were a physician — which I’m not — I would need to see you personally and run tests to make a responsible diagnosis, or prescribe any course of action. So I won’t even pretend to give you advice.

      However there are a few things that I can say in general:

      1. I would never take a dangerous supplement like Jack3D (DMAA or 1,3-dimethylamylamine). It is a powerful vasocontricting stimulant that has been banned in the U.S. and U.K. after being linked to multiple deaths.

      2. Macuna bean is an apparently natural source of L-dopa. Oliver Sacks wrote a great book (turned into a movie) called Awakenings about the brief euphoria of Parkinson’s patients who appeared to recover quickly on l-dopa, until they see the effect vanish and their symptoms return. In general, I am VERY skeptical of any medications or supplements because of the rebound effects and side effects. I prefer to finds ways to get my body to heal itself. Most often, that involves using some type of hormetic “stressor” to stimulate the body to get stronger.

      3. Asperger’s, as an autism spectrum disorder, has often been linked to digestive disorders. The common thread appears to be a malfunctioning immune system. I think the most interesting perspective on autism is the explanation provided in the wonderful book, “An Epidemic of Absence” by Moises Velasquez-Manoff. I’ve written about the thesis of that book in my article, “What causes allergies and autoimmune disease?“. I suggest you get that book and read especially Chapter 11 about “Autism and the Superorganism”. The “superorganism” refers to the powerful role that gut microbiota play in the progression and reversal of autism.

      4. Along that line, here is an interesting discussion of autism, digestive disorders and probiotics. If I were in your shoes, the first lead I would pursue is having my gut microflora tested and analyzed. Based on the results, I would consider using probiotics, or even a fecal transplant, to restore health gut bacteria. I would also dramatically limit sugar and carbohydrate in my diet, and add the appropriate type of prebiotic soluble fiber, to help foster the “good” microflora. People have seen dramatic improvements with this approach:

      Good luck to you,


  25. Steve

    M.R. I was hoping it would help others googling around.

    Todd, thanks. I’m mainly interested in asking what nutritional agents enhance upregulation of leptin and dopamine receptors, and receptors in their pathways, I can include them in my diet? I’ve tried looking this up for maybe 15-20 hours with limited success. I did see a couple of pages on it in the past but I can’t find that either.

    I have been on pro-biotics (kefir, and now Sauerkraut) for this, and can attest to the great benefits, and also that it has to be kept up constantly as it seems to relapse , I imagine based on whatever underlying conditions kept the gut flora/down in the first place. It is a real pain to make these actually and I found most probiotics supplements are very inadequate, so I am looking at going with the one recommended in the book “Have you got the guts to be really healthy”.

    In matter of fact, I used to make a shake of Kefir rice milk, rice pristine powder, nutritional cofactors, coconut oil, mucuna bean and a single serve of jack 3d, that is why it worked so well (probably because I had lots of receptors back then too).

    Mucuna Beans actually are shown to have a restorative affect on, I just found out, a number of brain pathways. They appear to have substances that negate the negative affects of l-dopa on its own, and per unit of l-dopa have a higher affect. So maybe they effect the receptors too. I’ve tried to find dosages and information on side effects of long term usage in Indian medicine for use of Parkinson disease without success so far. Having just water another 20 hours on various research in the last week or so, I have to lay down the computer and get back to reality while I’m well enough. I don’t know if feeling the effect of it after three days of use is a sign of rebalancing hormone levels, or of upregulation, but I think it might be worth looking into for what you are looking at. If we can get stressors, diet and something like Mucuna working on receptors, then most people will be covered. It is a lot easier to exercise, take cold shows, and digest if dopamine is working properly.

    The reported problems with Jack 3D like supplements appears to be from serious misuse, where people are taking six times the amount, extracting the pure ingredient in massive doses for parties, or potentially doing many hours of high intensity work in hot conditions without proper hydration, like high army training courses in the sun without enough water and on who knows what else. However, using it too often it diminishes in effect anyway, so is no long term solution to anybody that is listening. I’ve heard guys tell me they curl up in the corner shaking after they use it, I never had that problem because with my low dopamine I probably had lots of receptors, and feeding in cofactors, rice protein and mucuna, I just weakened as my receptors went down. So that sort of thing might be OK in the proper amount once every one to two weeks, but I think protein powder with proper diet derived (not meant to be manufactured in the body) nutritional cofactors for the pathways to run at their best naturally, is best.

    Thanks again Todd.


  26. Steve

    Todd, I forgot, here is some neuro-genative research activity I have just found:

    Obviously I’m not going to keep up with the diet anytime soon, but eventually this avenue might lead to everybody being able to optimize their pathways.

  27. johnny quick

    Hi Todd,

    In the books “The Dieter’s Dilemma by William Bennett MD and Joel Gurin” and “How to Lower Your Fat Thermostat by Dennis Remington MD, Gerth Fisher PhD and Edward Parent PhD” the authors state that based on their research, set point can be lowered by:

    1. A daily continuous hour of large-muscle rhythmic activity at 70-80% of MHR

    2. Decreasing fat consumption (no more than 20% of total calories)

    3. Reduce refined carbohydrates (including sugar, as close to zero as possible)

    4. Increase complex carbohydrates (45 to 80% of calories)

    5. Decrease calorie-containing fluids (as close to zero as possible)

    6. Drink adequate amounts of water (at least 6 glasses a day)

    7. Eat in Harmony with the Weight-regulating mechanism (eat until satisfied, not stuffed)

    What is your opinion of these gentlemen’s contentions?

    • Todd


      I can’t say that agree with these authors. Most of their recommendations may deliver short term weight loss, and may reduce leptin levels transiently. Gut there is little in their recommendations that will affect either the hypothalamus (our biological thermostat) centrally, or receptor levels in peripheral tissues like muscles. And without change regulation, a temporary weight loss will be met with increased drive to eat more or conserve energy by becoming less active.

      I would divide their list into three categories:

      A. May reduce set point:
      – Reduce refined carbohydrates, including sugar, as close to zero as possible. (Although I would intermittently break this rule to avoid over-adaptation)
      – Decrease calorie-containing fluids (as close to zero as possible)

      B. Neutral or worthless in the long term
      – Exercising at 70-80% of maximum heart rate. This may have a slight benefit, but the real benefit is at 90-100% of MHR for short bursts, and resistance exercise with heavy weights
      – Drink 6 glasses a day of water. This is overblown and has been debunked
      – Eat “until satisfied, not stuffed”. This is a good idea, but a hard habit to learn and easy to fall out of. Better to eat foods that are inherently satiating. Try eating potato chips “in harmony with the weight-regulating mechanism”

      C. Probably will increase set point:
      – Decreasing fat consumption to less than 20% of calories. Fat should be more than 50% of calories — but never in combination with carbohydrates. Best fats are mono-unsaturates like olive oil and shorter saturates like butter and coconut oil, with occasional modest intake of PUFAs. I would avoid linoleic acid found in safflower and corn oil
      – Increase complex carbohydrates to 45-80% of calories. A terrible idea. “Complex” carbs like bread, pasta and potatoes still turn to sugar, even if somewhat more slowly. The carbs to emphasize are soluble fiber and perhaps resistant starch — these are fermented to fats by gut microbes. So eat your carbs as non-starchy vegetables

      I would like to see the authors’ research and studies behind their claims that their recommendations lead to actual changes in the hypothalamus, GLUT4 or insulin receptors — or lead to sustained weight loss if followed.


      • johnny quick


        You mentioned “resistance exercise with heavy weights.”

        Could this be substituted with isometrics (as shown by research at Germany’s Max Planck Institute:

        or calisthenics (i.e. handstand pushups, one armed pullups, one leg squats)?

        • Todd


          Yes, I probably should have written “resistance exercise against a large force”. Isometrics and body-weight exercises can be very effective in taxing the fast-twitch muscles to increase strength and mitochondrial biogenesis.

      • johnny quick


        The aforementioned books contain a glossary of research to supposedly support their contentions.

      • branl

        Hi Todd, I have been sprinting, fasting, strength training, But I have depersonalization symptoms ie the world appears unreal it seems distorted, and I have trouble with my sense of sel and numbness etc, I also have trouble sleeping every night, even after extreme training and the lack of sleep seem to make everything worse, and makes me depressed. I dont go out much, and my social contact is pretty low, due to lack of friends, and no job, lack of money etc…

        I have done what you suggested ie sprinting, fasting, baths, but the sleep is still a issue, aswell as some depersonalization symptoms and depresed moods…could this be situational? ie the lack of job, money? or lack of social contact?

        many thanks

        • Todd


          Your question is a difficult one to answer. Depersonalization symptoms can arise from a wide variety of causes — from anxiety, disordered sleep, drugs and alcohol to complex social and psychological circumstances. I would suggest getting professional help. There is some evidence that cognitive behavior therapy may be effective:

          • Branl

            Many thanks, I do exercise, ie walking, running, strength training. I dont do drugs,no drink, no smoke, But it hit me when I found my self unemployed and unable to get work, which caused me to feel these odd symptoms…

            Yep its a real difficult as its not always very bad, but on and off days were those dissociate symptoms hit me….

            thanks again

  28. mry

    Hi Todd,

    I’ve been wondering about your standpoint on the following topics. I know the answer to most of it would be “it depends”, but I would like to hear your thoughts anyway.

    1. How long does it take to upregulate dopamine receptors to see a significant change on the condition you’re following regime rigolously (avoid sweets, strenuous exercises daily, protein intake, once per week of 24h intermittent fasting). Would it be 1,2,3 monts, 1, 10 years?
    2. Is there an upper limit to the number of receptors you can upregulate.
    3. Is age a factor in this? For older people body and receptors degrade. How far is degredation in your opinion?

    • Todd

      As suggested in the NEJM article and other references, receptor upregulation of receptors begins within hours of intense exercise or fasting. However, large and sustained increases in receptor density usually take several weeks. This is also true of other G-coupled protein receptors such as those for insulin and leptin. Of course there is an upper limit based on biology, genetic variation and age. Loss of receptor sensitivity is always reversible, so it is definitely worth making the effort to re-sensitize your receptors. Age is not a limiting factor! You’ll proceed faster if you do IF more frequently than once a week and exercise intensely 1-2 times per week.

  29. Steve

    Johnny. thanks for that.


    Well on massive probiotic home made kefir rice milk and probiotic organic sauerkraut and velvet bean. Despite a few complications and viral illness break out, things are getting better and I got my strength back. Tried cold showers but the water is only cool half the year.

    It is very difficult to tell what is causing what in these things due to interaction between the receptors, weak binding, receptor neutralization, receptor repopulation, hormones and between the hormone pathways. I’ve read that various things will knock out receptors or cause growth. A hormone might interact and adjust another hormone pathway, such as in the testosterone pathway, dopamine and serotonin which interact with at least a third pathway etc. Todd, could you give a basic description of how these things work, and how to tell which is happening at any particular time, as due to the interactions in particular state of interaction should result in a particular state of being. To put simply, that any particular thing is going to produce a fingerprint that accounting for the state of over systems that interfere with it, should give the actual state. Maybe a good article. even if there are bits that leave out because you don’t agree with it.

    I’ve read about various mental illnesses that are receptor based (others digestion biotic and liver based), and I know a few people.



  30. Kathy

    Hi Todd,
    I’m wondering if following your suggestions to upregulate receptors would also work to downregulate? I suffer from migraines and have found out my problem is dopamine receptors that are too sensitive.

    This is the study that talks about it in case your interested;


    • Todd

      Very interesting article, Kathy. I learn something new every day, from those like you who post interesting information here.

      My first reaction is that this hypothesis — that migraines are linked to excessive or oversensitized dopamine receptors — is interesting, but not fully substantiated. It’s still a hypothesis. It might occur in all those with migraines, or in certain subsets of migraine sufferers. It could be causally related — or a mere correlation. So you can’t be sure whether or not it applies to you.

      I would ask certain questions. If you have a heightened sensitivity to dopamine, that might suggest that you have pleasureable experiences, that you are generally either happy or anxious, and that you are definitely not depressed. It would suggest that you are probably not overweight and that you have a high energy level bordering on being high-strung. Do these characteristics match your persona?

      But let’s suppose that the hypothesis is correct and that it applies in your case. So you want to dial back your dopamine receptors. Does that mean you should try to block or “antagonize” your dopamine receptors? The article you linked proposes:

      From this perspective, a blockade of dopaminergic hyperresponsive receptors can be considered as a rationale for the therapy of migraine.

      The problem with blocking dopamine receptors is that it can paradoxically upregulate them. Do some searches on “low dose naltrexone” and you’ll learn how blocking dopamine receptors can actually result in an increase in the number or sensitivity of dopamine receptors. This therapy has been found useful in overcoming alcoholism and other addictions, for example.

      If you want to actually block dopamine receptors, that should be relatively easy. Do the opposite of what I normally advise. Eat foods that promote insulin resistance, such as those that contain fructose and linoleic acid. Eat french fries and sugary starchy foods. Don’t exercise. Drink alcohol. Cut out caffeine. I’m being a bit facetious here, but not entirely.

      In short, I don’t know the answer to your question. The hypothesis in the paper may be entirely wrong, or only partially correct. Don’t take it as the gospel truth. But it is an interesting piece of information. Think about how your own personal experience either corroborates it, or disconfirms it. Articles like this are a starting point for further investigation, not a fait accompli diagnosis.

      Hope that helps or at least riles you up.


      • Kathy

        Thanks for the reply Todd.
        I came across the above article by accident but was very excited when I started reading it since I have practically all the symptoms it listed. I’m definitely not interested in medication. Covering up some symptoms only to give me more later doesn’t appeal to me and especially not after reading your article. I’ve decided to try your advice in the article and see what happens…(not the french fry part!) 🙂 I’ll let you know what happens.

        • Todd

          Kathy. Glad to hear the article resonates with you. Please do report back on your results — positive or negative. — Todd

  31. Steve

    Todd, here is an interesting site that follows and links research on supplements. Unfortunately they are not up to scratch on the whole Leptin receptor thing. Just select the search function and type in the subject to search for. The articles are usually nicely divided with various summaries tools.

    Thanks again.

  32. Steve

    Hmm, I forgot, that particular article is curtailed to get people to buy their book, most articles are there full though. What they are doing takes a lot of effort.

  33. Giorgio

    Hi Todd, thanks for your insightful informations. Really appreciate what you describe and suggest in your blog post.

    I’ve been wondering about your standpoint on the strenuous exercise cycling. I know the answer here would be “it depends on your physical training level”, but I would like to hear your thoughts about the frequency of your training sessions within a week, and how the scheduling is arranged monthly. Do you have any directions about training session duration?

    Thanks again Todd.

    Best regards, Giorgio.

    • Todd


      I’m not a cyclist or trainer, so I can’t suggest any specific training protocol. In general, I like the idea of circuit training — workouts of different lengths, intensities, terrain, etc., with adequate rest periods built in. Of course, it has to be individualized, so what works for one person may be too strenuous or too light for another. One way to know whether you are overtraining is to get an HRV (heart rate variability) monitor. Many athletes have found this is an excellent way to detect overtraining.


  34. Shane


    I love your website. Can you think of an application to this theory when it concerns trying to get over a relationship that is over, specifically a friendship? I tend to ruminate over bad memories concerning the negative things we said to each over and I sometimes cling to false hope that we can reconcile.

    I tried doing loving-kindness meditation which helps me to forgive but any practical tips for possibly using this for negative rumination and for learning to let go? Thank you so much.

  35. Ferhat

    Hello Todd

    (sorry for my poor English, as I am originally Turkish)

    You are doing a great favor to us. Thank you sincerely.

    I am 29 years old phisically healty male. My weight is normal. I am diagnosed ”attention deficit disorder” about 3 weeks ago.

    I always had issues of low concentration, procrastinating evertyhing untill the last moment, not being able to start working for simple tasks for long time, going on mind journeys in middle of important moments, feeling confused most of the time, intellectual instability, weak short term memory, avoidance of tasks that require intensive mental working, not being able to work without drinking coffee and so.

    Many years ago, in the beggining of college, while I was around age of 19-20, I started to realize that I had some problems that restrain me to use my itellectual capacity and intelligance in all areas of life.

    I started to make personal searches, such as checking hormone levels (testosterone, dha…), and they were normal. Many other tests, many other health check ups even cancer check ups. There was nothing wrong with me phisically. I even had a sleep disorder checks, which resulted normal too. After all, I visited a psychiatrist and told him my complaints, and I have been prescribed ssris (cymbalta), that I used for a month, but didnt not make any affect to my symptoms (execpt feeling too good generally).

    Anyway , 3 weeks ago, another psychiatrist, did some tests to me and diagnosed me ‘attention deficit disorder’ , and he prescribed me 36 mg ‘Concerta’ (methylphenidate) for every day use. I took the concerta and all my complaints went away on 1st day, I used the medicine for a week, it was amazing, but then it scared me. Because it is not curing my disease, it is only curing the symptoms. I was happy with eliminated symptoms because I was able to perform %100 of my capacity. But being dependent to a medicine for all life, has scared me so much. Besides, as per my researches on the web, I found out that methylphenidate is a chemical that has similar affects on brain as the Cocaine do, and long term side affects of methylphenidate are not so clear as per my reasearches, and there are many people complaining for its long term side effects. Their complaints are; not being able to stop taking the medicine, when they stop they complain that very bad ADD symptoms appear at 1st day, which are even worse than the time before they even started the medicine. Some are complaining developing tolerance to methylphenidate accordingly unressistable necessity to increase the dosage seriously. And the stories goes on…

    After my searches on the web, I found out that dopamine receptor level in the brain is as important as the dopamin level itself. I think my problem can also be related to dopamin receptor level in my brain. When I was born, my mother could have breastfeed me only for 2 months, because 2 months after I was born, she was pregnant to my sister, and during my sister’s pregnancy, she didnt have any milk in her breasts so far to feed me. So I started to believe that the reason of my ”attention deficit disorder” can be not being breastfeed enough from my mother.

    I used to have porn and accordingly masturbation addiction since my puberty time, which I believe also has great affect to my dopamine and receptor problems in my brain. In last 2 weeks, I also did quit at all watching porn and masturbating. This is not easy but I did it, no watching port, no masturbation for 2 weeks at all, and I am decisive. No way back to porn and masturbation. I am removing all easy high pleasure giving thing from my life, in order to get better and cure my attention deficit disorder.

    My question to you is; instead of having a life addicted to methylphenidate and taking the risk of severe side affects on long term, can I beat this life consuming disease by natural ways such as you mentioned in your above article ?

    On the other hand, through me researches, I have come across to the articles saying that some fat acids dietary supplements such as phosphatidylcholine, phosphatidylserine, inositol can have great positive affect on increasing (cure in my case) the brain functions. Do you agree ? Do you suggest them too ?

    I can imagine how time is valuable for you but your negative/positive/detailed any comment will be very appreciated and will be very helpfull to me.


    • Todd


      As you surmise, problems with ADD and addiction to porn, food and other pleasures can stem from down-regulation of dopamine receptors. Your honesty, persistence and desire to free yourself of lifelong dependence on medications is admirable. The trap of dependence on medications such as SSRIs is described very well in a book you might want to get — Anatomy of an Epidemic. The author, Robert Whitaker, describes how antidepressants and other psychiatric medications provide short term benefits, but in the long term have the opposite effect, making the problems worse. You can watch the short YouTube video too.

      You can overcome your dependence on medication and addiction for pornography, but it is a hard road — at least in the beginning. You’ll experience the pain of withdrawal, but with time you’ll regain natural pleasure and peace. To make the process go faster and re-sensitize your dopamine receptors, you should deliberately expose yourself to difficult and even strenuous challenges — intense exercise, cold water, and short periods of fasting. You’ll have more success if you do this gradually, in small steps.

      You may want to check out an excellent website for those who are giving up pornography addictions. The men on these sites find that abstaining causes “rebooting”, allowing them to overcome erectile dysfunction, re-establish intimate relationships, and generally increase the pleasure in their lives. Besides merely abstaining, they have found that challenges like cold showers help a lot:

      Regarding supplements, this is something you should definitely investigate. Some people find that PC and PS help; also, omega-3 fatty acids from fish oil supplements can improve brain function and reduce ADD symptoms.

      The best advice I can give you is to be patient and persistent. Unlike medications that give immediate relief, the method of Hormetism — gradual exposure to increasing natural stressors — takes time, often several months, before you really experience the benefits. But you’ll be happier for it.

      Best wishes,


  36. Bij'

    And how about using salvia (potent kappa opioid agonist) as a stressor to create anxiolithic/antidepressive effect (positive adaptation)? High dose salvia are known to produce dysphoria and rebound antidepressive effect (afterglow). Isn’t the principe of hormesis here?

    Why not look at chemical means to create positive stress? Salvia is basically non toxic. I am a drug user addict(not physically) and can attest that interval training, and fasting are useful “feel great” activities that I use extensively to manage my drug use. But I’m searching more potent ways to fight against anhedonia and drug reward cravings, because it isn’t enough. (I started cold showers a few days ago hehe)

    Meditation, aka learn to not react to impulsions is useful too, but I feel it difficult to practice everyday when still using drugs weekly. I did 2 hard core 10 days meditative retreats (vipassana style) but it wasn’t miraculously useful for drug cravings and came back to my bad habits after a few weeks.

    A little study I found interesting about salvia and dopamine receptors :

    While specific D2 agonists are hard to come by [such as bromocryptine], Salvinorin A is a good example of the effects of D2 dopamine receptors. While the entirety of the unpleasant effects of Salvinorin A are due to its Kappa Opioid receptor agonism, the psychedelic effects are entirely due to D2 receptors. Salvinorin A is both a strong D2 agonist and a Kappa Opioid agonist. The Kappa Opioid receptor not only shuts down dopamine neurons in the area affected by opiates, but also very strongly upregulates D2 receptors. This means by being a Kappa Opioid agonist, Salvinorin A potentiates its psychedelic action at the D2 receptors.

    The D2 dopamine receptor does not produce euphoria. It produces the following:
    – Dissociation, similar to NMDA antagonism but not as thorough. It separates you from the outside world, giving you an inability to communicate or interact with it. This is due to changes in calcium levels affected by D2.
    – Suppression of dopamine release in the body. This is related to dissociation: it disconnects you from the organic movement of your body. You literally move like a robot. Suppression of dopamine release in this case does not mean dysphoria, it simply occurs in the movement coordination areas.
    – Closed Eye Visuals: At lower levels, two dimensional cartoon like artwork appears. Examples can be found on google. The artwork is present both in cannabis, and in salvia at low levels. At higher levels things get more visionary, as evidenced by salvia.
    – Open Eye Visuals: At lower levels, D2 makes the entire world lose its sense of three dimensionality. It makes everything flat, yet somehow interconnected. It makes objects blurry and lose focus, and prevents your eyes from locking onto objects.
    – Mind’s Eye Visuals: Faces, numbers, and diamonds can be perceived. Waves of sky blue energy.

    Downstream effects:
    D2 very strongly stops the long term production of prolactin. When this happens, you regain the feeling of childhood magic that was lost when you became a teenager. Reality opens up to you. Things become FRESH. Prolactin suppresses global dopamine release in a way that suppresses how you felt as a child, the innocence you once had. This is one of the primary reasons phenethylamine is so tonic and antidepressive. Prolactin causes depression, and D2 relieves prolactin.

    I apology for my bad english and hope I’m understandable, thanks a lot for all the usefull information on your webside. 🙂

    • Todd

      Use of D2 agonists at low levels can produce pleasure or activating effects on those with low dopamine levels, e.g. those with Parkinson’s disease. And as the article suggests, at high levels they can produce psychotropic or schizophrenic effects.

      I don’t see how this is an example of hormesis, since it involves direct stimulation of receptors, rather than sensitization or up regulation of receptors via “stressors”, e.g. physical exercise, challenge, fasting, or temporarily refraining from certain pleasurable stimuli.

  37. Hi and thanks so much for this excellent information on the importance of receptors and how to balance them. Can I ask if you have any further suggestions as to how to manage serotonin receptors?

    • Todd

      To up regulate serotonin receptors, refrain from actions that provide excessive serotonin. One way to do this is by restricting carbohydrates or the combination of carbohydrate and tryptophan rich foods. This is the opposite of what is usually urged! For example, DesMaisons, in her book “Potatoes, Not Prozac” urges consuming potatoes in combination with proteins like turkey to provide the raw materials the body uses to synthesize serotonin.

      While this will indeed provide short term benefits by elevating serotonin levels, this can have the long term effect of down regulating serotonin (5-HT) receptors! By turning this logic on its head, one expects that generally restricting carbohydrate and tryptophan rich foods can upregulate 5-HT receptors, and hence sensitivity to serotonin. Then — after one is “desensitized” — periodic or intermittent consumption of moderate levels of carbs and protein will be sufficient to generate sufficient serotonin to “satisfy” the desensitized 5-HT receptors.

  38. Bij'

    Use of D2 agonists at low levels can produce pleasure or activating effects on those with low dopamine levels, e.g. those with Parkinson’s disease. And as the article suggests, at high levels they can produce psychotropic or schizophrenic effects.

    I don’t see how this is an example of hormesis, since it involves direct stimulation of receptors, rather than sensitization or up regulation of receptors via “stressors”, e.g. physical exercise, challenge, fasting, or temporarily refraining from certain pleasurable stimuli.

    I see euphoric drugs like stimulants and opiates as the antithesis of hormesis : By creating pleasure, they weaken your biological ways to fight against stress, and this is materialised by desensitize your dopaminergic system, increase amygdala sensitivity etc…

    Salvia is a psychedelic drug that do the very opposite : Resensitive your dopaminergic system by D2 agonism and opioid kappa agonism. A few studies report antidepressive effect of salvia, but not like benzodiazepines and SSRI. Salvia is know to be a very disphoric drug in the principal effects (contrary to benzodiazepines), but after the experience you feel “rejuvenated”. I think this is like interval training, hard when you do it, but worth the effort.

    In this case, salvia is a positive stressor and I don’t understand why this is not like hormesis! In a pharmaceutical view, it’s like refraining from pleasurable stimulis. Do you dismiss entirely pharmaceuticals means to upregulate receptors here? Aren’t “psychotropic or schizophrenic effects” of salvia a blessing in disguise here? I was personally interested if we could have the beneficial effects of upregulation of receptor, with the minimum psychedelia (low doses salvia). Chronically take an hallucinogen is a no-no for obvious reasons ^^

    Hope you understand better what I was trying to say. Also, I apology if you don’t want to talk about drugs here, but according to me we have to watch all the means possible to treat a problem with an open mind. I totally agree with you when you say that naturals stressors (sport, cold, etc…) are of great significance to fight against addiction (Felt it first hand).

    Again, thanks a lot for your great informative blog! *go to take a f**k horrible cold shower* 😀

    • Todd

      Hi Bij,

      I’m not against drugs, herbs or other ingestibles that might hormetically upregulate helpful metabolic, immune, or psychological receptors. For example, low dose naltrexone may have precisely such a beneficial action. My only question was whether Salvia specifically acts that way. It is said to be a D2 agonist, and I understand an agonist to be a compound that activates a receptor by binding to it, thereby increasing the output signal. So I reasoned that because Salvia increases the net “dopamine signal”, this ultimately would lead to homeostatic downregulation of the D2 dopamine receptor. But perhaps I have this backwards, since you say that salvia is dysphoric in the short therm, but leads to subsequent “rejuvenation”.

      The other complicating factor is that Salvia is also known to be a kappa-opioid receptor agonist. Since it acts via multiple modalities, it may be hard to say for sure whether there is a net hormetic/hedonic effect.


  39. Bij'

    D2 receptors family and D1 receptors family are kind of “opposite” in their effects. They are both G protein coupled receptors, but an agonist at D1 receptor will increase cAMP, and an agonist at D2 receptors will decrease cAMP. That’s why salvia (D2 partial agonist) don’t create pleasure, other D1 agonists like amphetamine do. Salvia is also a kappa opioid agonist, but again no euphoria to find here : There are 3 principal opioid receptors, mu, delta and kappa and hedonistic feeling are linked to mu agonism. I quote wikipedia for kappa opioid receptor agonism (that’s why I was so interested about salvia):
    [quote]The KOR may provide a natural addiction control mechanism, and therefore, drugs that act as agonists and increase activation of this receptor may have therapeutic potential in the treatment of addiction.[/quote]

    But I confess that my understanding of this subject is only partial.

    This is interesting for naltrexone. In a same way, I personally used memantine low doses(an NDMA antagonist chemical like ketamine) with great success to fight against physical tolerance to GHB (an I know that it can work for others substances like stimulants and opiates). The problem is that I think we are taking away from your “hormenism” : It was working for GHB tolerance, but the mental addiction part was still intact. No effort needed here, just pop a pill of memantine and you will gradually have to reduce your dosage.

    I think the mental part of “confronting to discomfort” is really important for addictions problems. Memantine help just for the physical/physiological part of the addiction problem, without mental effort. Salvia is antiaddictive, even if you like the psychedelic part, you have to make an “effort” to take it, like climbing a mountain. I feel that these products and their different effects have to be distincted. And for the mental part, I think hormenism is the way to go, face fear etc… 🙂

    Anyway I hope this is not off topic! Have a nice day!

    • Todd


      Thanks for the very good explanation. I didn’t realize that the D1 and D2 receptors worked in opposing fashion. So this now makes more sense. See, I learn something new every day, often from the comments here on this blog.

      I think you make an excellent point that pill-popping can never really substitute for for effort: “the mental part of ‘confronting discomfort”’ is really important for addiction problems.” You need to feel discomfort or effort to truly change behavior, and this may be particularly important for overcoming addiction.


  40. moises

    I believe the book you cite is titled Dr. Bernstein’s Diabetes Solution. It is not Dr. Bernstein’s Diet Solution. You might want to state the edition, since there are a few of them.

    • Todd

      Thanks for pointing out the typo, now corrected. Couldn’t immediately find my personal copy, but it is the 1997 edition.


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