4-Caffeoyl-1, 5-quinide

4-Caffeoylquinide

4-CQL

4-Caffeoyl-1, 5-quinide

no

no

4-Caffeoyl-1, 5-quinide

Canadian researchers report on their tests of various components of coffee. They find that phenylindanes, which are breakdown products of the coffee bean during roasting, are highly effective in vitro at reducing the aggregation of of the amyloid beta and tau proteins which, when aggregated, drives the spread and neurological destruction of Alzheimer's disease (AD)



This, combined with prior research on the apparent protective effects of coffee regarding AD means that it drinking coffee, decaf or not, may significantly protect against this terrible neurodegenerative disease.



[#timeline]

The initial research was done in 1983 by a team here in Melbourne, Australia. The research was judged to be significant enough that they were able to publish their initial paper inThe researchers tested a variety of foodstuffs to find if they contained any compounds which bound to the mu opioid receptors (MOR) in rats. This was done by, first of all, exposing the receptors (in a brain homogenate) to radioactively labeled naloxone, which is a mu opioid receptor antagonist with a high affinity for the receptor. When the foodstuff was mixed into the homogenate, the degree to which any compounds bound to MOR in preference to the naloxone was assayed by measuring how much radio-labeled naloxone was displaced from the receptors and so went into solution.The abstract is:Later research indicates that the most significant of these compounds appears to be 4-caffeoyl-1, 5-quinide, as illustrated above. This is according to its affinity for the receptor and its concentration.Following the initial paper mentioned above, some of the same researchers made progress determining which compounds in coffee were binding to the MOR. They applied for a patent in 1986. I am not sure about the status of this, but perhaps this is a patent application rather than an actual patent:Some of the team wrote a paper in 1987 (I don't have a copy of this) with more details of the antagonist compounds:I have not done a full literature search on this subject, nor have I exhaustively read and analyzed these papers, so I have probably not mentioned some significant papers in the 1990s. The next one is highly significant, from 2004. It is by a team of researchers at the Vanderbilt Institute for Coffee Studies: http://vanderbilt.edu/ics/ The most active compound according to its affinity and concentration is is "4-Caffeoyl-1, 5-quinide" AKA "4-Caffeoylquinide" AKA "4-CQL" (Table 1 and page 151). This constituted 0.78% of the coffee extract. In the conclusion:From the same team, in 2005:This shows the chemical structure of "4-Caffeoyl-1, 5-quinide" on page 1506. I copied the image into the above graphic.Also from the same team, in 2006:This lists (Table 3) the proportion by dry weight of 4-caffeoyl-1,5-quinide in various coffees. The values are around 1 part per thousand.There's no new research in this, but in March 2015, the Journal of Caffeine Research published a letter I wrote concerning these compounds, the importance of recognising that caffeine is not the only active compound in coffee, and the impact of these compounds on Restless Legs Syndrome:See an update to this regarding caffeine and restless legs syndrome: ../rlsd/briefsumm/#ccc

Compounds of general formula (I), wherein one of the R 1 , R 2 and R 3 groups represents a feruloyl or isoferuloyl group of formula (II) or (III), respectively, and the other R 1 , R 2 and R 3 groups represent hydrogen. These compounds have opiate receptor activity and may be used in treatment of the toxic effects of opiate narcotic analgesics. Preparation of these compounds by extraction from coffee, and by synthetic processes is disclosed.

Opiate receptor-active peptide fragments (exorphins) have been identified recently in casein and gluten hydrolysates, and morphine has been found in bovine and human milk. To determine whether similar peptides or alkaloids occur in other foodstuffs, we have screened potential sources using a rat brain homogenate assay to detect opiate receptor activity. We report here that instant coffee powders from a variety of manufacturers compete with tiitiated naloxone for binding to opiate receptors in the rat brain membrane preparations, with no significant difference between normal and decaffeinated coffee. The receptor binding activity resembles that seen with opiate antagonists, in that there was no change in the half-maximal effective dose (ED 50 ) in the presence of 100 mM Na + ; on bioassay, the activity was similarly shown to be antagonistic and specific for opiate-induced inhibition of twitch. Preliminary characterization of the activity reveals that it has a molecular weight (MW) in the range 1,000–3,500, is heat-stable, ether-extractable, not modified by enzymatic digestion with papain, and clearly separable from caffeine and morphine on TLC. As its concentration in an average cup of coffee is five times the ED 50 , these data suggest that drinking coffee may be followed by effects mediated via opiate receptors, as well as effects of caffeine.

This and the next section contain my analysis.The above peer-reviewed journal articles report that coffee contains one or more compounds which act as opioid receptor antagonists, in vivo, in rats. It is reasonable to consider that these compounds may have much the same effect in humans who drink coffee.In late 2011, I searched for "caffeoyl" and "caffeoylquinic" in two places, both of which are representative of current research and knowledge in the pain field. I found no mention of either word.I wrote to the editors about this and received an appreciative reply that they would look at the papers cited above.

Here are some figures for the caffeine content of non-decaf coffee.Some figures for caffeine content of decaf coffee:Here are some calculations for the amount of caffeine in decaf coffee as a percentage if the amount in non-decaf coffee:A 2011 recent papercontains the following information, with my red figures indicating the percentage caffeine remaining.Eyeballing these percentage figures, I think a reasonable guesstimate is that. This is based on the figures in red above which are mainly in thetorange. However, there may be some outliers which haveor more of the caffeine of regular coffee.References for this section:

Donahue , Patricia J McLaughlin and Ian S Zagon

Low-dose naltrexone targets the opioid growth factor–opioid growth factor receptor pathway to inhibit cell proliferation: mechanistic evidence from a tissue culture model

Exp. Biol. Med. 2011 ;236:1036-1050

doi:10.1258/ebm.2011.011121

http://ebm.rsmjournals.com/cgi/content/abstract/236/9/1036

Renee N, Patricia J McLaughlin and Ian S ZagonExp. Biol. Med.;236:1036-1050doi:10.1258/ebm.2011.011121

The response to opioid antagonist administration is compensatory upregulation in the production of opioid peptides {endogenous opioid receptor agonists} and opioid receptors.



The exogenous opioid receptor antagonists in coffee have unknown half-lives in the blood (serum) and in the CSF (cerebro-spinal fluid, in which neurons are bathed) in various parts of the CNS (central nervous system: the brain, brainstem and spinal cord). So we don't know how long they reduce the activation of opioid receptors for.





We don't know to what degree they affect different types of opioid receptors.





We don't know to what degree they cause increased production of the various types of endogenous opioid receptors in various parts of of the CNS or how these variations change over time.





Similarly, we don't know how they affect the upregulation (increased numbers of) opioid receptors, of various types, in various parts of the CNS, over varying time periods and according to the dosage.



(End of update.)

RLS / PLMS / RLSD

Restless Limbs Sensorimotor Disorder because I believe this should be the new name for Restless Legs Syndrome (RLS) combined with Periodic Limb Movement Syndrome (PLMS).



RLS/PLMS symptoms are well known to be inhibited by opioids. The term "opioids" on its own generally means any endogenous compound, or exogenous synthetic or naturally occurring compound which has an affinity for opioid receptors and which activates them. A more precise statement is: RLS/PLMS symptoms are well known to be inhibited by opioid receptor agonists.



Opioid receptor agonist drugs are widely used to control the symptoms, usually as a second line or in combination with the first line of defence which are dopamine receptor agonist drugs. For more information in general about RLS, see the links at my page



Since opioid receptor agonists prevent or reduce RLS/PLMS symptoms, we can reasonably expect that exogenous mu opioid receptor (MOR) antagonists would make RLS/PLMS symptoms worse.



My wife Tina has suffered from RLS/PLMS since she was a child in Texas. She hasn't been drinking full-strength coffee for a few years. Her RLS/PLMS was frequently bad to the point of being intolerable when she did. This year (2011) she firstly reduced her decaf coffee and later stopped drinking any coffee at all. She has not been drinking any other caffeinated drinks for several years. Decaf contains significant caffeine, and caffeine is well known to disturb sleep and contribute to RLS/PLMS. As noted above, I estimate that decaf typically has 4% to 6% of the caffeine of regular coffee, but there would be considerable variation outside this range.



What we observed seems to result from something beyond the low levels of caffeine which remain in decaf coffee. I think the effects of three cups of tea a week (a cup of tea contains about 40mg of coffee, much more than a typical decaf coffee) probably would not have contributed so strongly to RLS/PLMS symptoms as the three decaf coffees.



When she cut back from several decafs a day (two or three, but some were made with a home percolator and stronger than average) to three a week, her RLS/PLMS disappeared for about three weeks, and then gradually returned to a much lower level.



This is all with no caffeinated tea or any other caffeinated drinks - though she still eats a little chocolate, which contains a small amount of caffeine and a larger amount of a similar compound, theobromine, which seems to be much more benign.



A few months later, when she went from three to zero decaf coffees a week, a similar thing happened: RLS/PLMS disappeared for about a week and then gradually returned to a still lower level.



Now, her RLS/PLMS problems are a minor and uncommon occurrence, maybe once a week or so. This is far better than having it most nights. (However, there were periods in the past when she was drinking coffee when there was little or no RLS/PLMS, so we are not aware of every variable.)



I think these observations are consistent with my hypothesis that the continual level of exogenous MOR antagonists due to three decafs a week, or before that three or so per day, resulted in higher general background levels of endogenous opioids, but not enough to fully compensate for the antagonism of whatever opioid receptors are involved in RLS/PLMS.



When Tina cut down to three decafs a week, the exogenous MOR antagonists suddenly dropped to a fraction of their former level (I am assuming a half-life such as a day or less). Then her body was still producing, or at least still had circulating reserves of, a relatively high background level of endogenous opioids. I guess this would take a few weeks to return to normal levels.



During those few weeks, I would expect the opioid receptors to be more activated than normal (normal = no exogenous MOR antagonists in the last few months) because the higher than normal, and slowly declining, endogenous opioid level was not opposed by significant quantities of exogenous MOR antagonists. So this explains why RLS/PLMS symptoms became less prevalent than normal after going from three a day to three a week, and became less prevalent again after going from three a week to none.



Can anyone report experiences with RLS/PLMS and coffee, especially going from decaf coffee and no other caffeinated drinks to zero coffee? Is there anyone with severe RLS/PLMS requiring medication who does not use any caffeine, coffee, or any other drugs which might contribute to the symptoms? Please let me know:





Sir Thomas Willis (



Wherefore to some, when being abed they betake themselves to

sleep, presently in the arms and legs, leapings and contractions

on the tendons, and so great a restlessness and tossings of other

members ensue, that the diseased are no more able to sleep,

than if they were in a place of the greatest torture.



According to:



http://www.nestleprofessional.com/uk/en/SiteArticles/Pages/History_of_Coffee.aspx



"In the UK, the first coffee house opened in 1650 in Oxford. The

first London coffee house opened in 1652 in St Michael’s Alley,

Cornhill. Lloyds of London was originally a Coffee Shop called

“Edward Lloyds Coffee House”. London coffee houses were

nicknamed “Penny Universities” because for the price of a cup of

coffee you could sit and join in the stimulating conversation with

the great thinkers of the day. Jonathon’s Coffee House in Change

Alley was frequented by entrepreneurs and merchant venturers,

and was the beginning of the London Stock Exchange. By 1675

there were nearly 3,000 coffee houses in England."



The page



So it seems that the unfortunate RLS sufferers Willis observed could have been coffee drinkers.



Later in 2011, I intend this site to have comprehensive material on what I am callingbecause I believe this should be the new name for Restless Legs Syndrome (RLS) combined with Periodic Limb Movement Syndrome (PLMS).RLS/PLMS symptoms are well known to be inhibited by opioids. The term "opioids" on its own generally means any endogenous compound, or exogenous synthetic or naturally occurring compound which has an affinity for opioid receptors and which activates them. A more precise statement is: RLS/PLMS symptoms are well known to be inhibited by opioid receptor agonists.Opioid receptor agonist drugs are widely used to control the symptoms, usually as a second line or in combination with the first line of defence which are dopamine receptor agonist drugs. For more information in general about RLS, see the links at my page ../rlsd/ Since opioid receptor agonists prevent or reduce RLS/PLMS symptoms, we can reasonably expect that exogenous mu opioid receptor (MOR) antagonists would make RLS/PLMS symptoms worse.My wife Tina has suffered from RLS/PLMS since she was a child in Texas. She hasn't been drinking full-strength coffee for a few years. Her RLS/PLMS was frequentlyto the point of beingwhen she did. This year (2011) she firstly reduced her decaf coffee and later stopped drinking any coffee at all. She has not been drinking any other caffeinated drinks for several years. Decaf contains significant caffeine, and caffeine is well known to disturb sleep and contribute to RLS/PLMS. As noted above, I estimate that decaf typically has 4% to 6% of the caffeine of regular coffee, but there would be considerable variation outside this range.What we observed seems to result from something beyond the low levels of caffeine which remain in decaf coffee. I think the effects of three cups of tea a week (a cup of tea contains about 40mg of coffee, much more than a typical decaf coffee) probably would not have contributed so strongly to RLS/PLMS symptoms as the three decaf coffees.When she cut back from several decafs a day (two or three, but some were made with a home percolator and stronger than average) to three a week, her RLS/PLMS disappeared for about three weeks, and then gradually returned to a much lower level.This is all with no caffeinated tea or any other caffeinated drinks - though she still eats a little chocolate, which contains a small amount of caffeine and a larger amount of a similar compound, theobromine, which seems to be much more benign.A few months later, when she went from three to zero decaf coffees a week, a similar thing happened: RLS/PLMS disappeared for about a week and then gradually returned to a still lower level.Now, her RLS/PLMS problems are a minor and uncommon occurrence, maybe once a week or so. This is far better than having it most nights. (However, there were periods in the past when she was drinking coffee when there was little or no RLS/PLMS, so we are not aware of every variable.)I think these observations are consistent with my hypothesis that the continual level of exogenous MOR antagonists due to three decafs a week, or before that three or so per day, resulted in higher general background levels of endogenous opioids, but not enough to fully compensate for the antagonism of whatever opioid receptors are involved in RLS/PLMS.When Tina cut down to three decafs a week, the exogenous MOR antagonists suddenly dropped to a fraction of their former level (I am assuming a half-life such as a day or less). Then her body was still producing, or at least still had circulating reserves of, a relatively high background level of endogenous opioids. I guess this would take a few weeks to return to normal levels.During those few weeks, I would expect the opioid receptors to beactivated than normal (normal = no exogenous MOR antagonists in the last few months) because the higher than normal, and slowly declining, endogenous opioid level was not opposed by significant quantities of exogenous MOR antagonists. So this explains why RLS/PLMS symptoms becameprevalent than normal after going from three a day to three a week, and became less prevalent again after going from three a week to none.Can anyone report experiences with RLS/PLMS and coffee, especially going from decaf coffee and no other caffeinated drinks to zero coffee? Is there anyone with severe RLS/PLMS requiring medication who does not use any caffeine, coffee, or any other drugs which might contribute to the symptoms? Please let me know: ../contact/ Sir Thomas Willis ( Wikipedia page ) wrote, in 1672 (English translation from the original Latin) what is now regarded as the earliest known description of Restless Legs Syndrome:According to:The page http://www.localhistories.org/population.html states that the population of England was about 4 million in 1600 and about 5.5 million in 1700. Interpolating these figures gives a population of 5.125 million in 1675. If there were in fact 3000 coffee houses, that would be one for every 1708 people.So it seems that the unfortunate RLS sufferers Willis observed could have been coffee drinkers.

Anxiety, conflict, irritability and aggression





http://www.nimh.nih.gov/health/publications/anxiety-disorders/index.shtml



Since caffeine, certain illicit drugs, and even some over-­the­-counter cold medications can aggravate the symptoms of anxiety disorders, they should be avoided.



This includes social phobias, any kind of anxiety disorder, especially OCD (Obsessive Compulsive Disorder). Its pretty obvious that anyone who struggles to contain aggressive impulses should avoid caffeine entirely.



Similarly, anyone with PTSD (Post Traumatic Stress Disorder) shouldn't be taking any drugs which makes them more anxious. They are already suffering intrusive thoughts which are typically irrational reverberations of traumatic experiences in the past. They re-experience the feeling of helplessness, pain and fear of being annihilated.



Caffeine has been shown to increase the rate of hallucinations in healthy people who are in a stressful situation. This paper from some researchers at La robe University, close to where we live:



Croce , J. Bart, S. Callow, J. D’Promontories, J. Dell’Orson, A. Di Clemente, K. Hanson, M. Valletta, S. Carlota's, B. Ivor's, L. McKenzie, R. Norman, A. Thieu, M. Mouldered, S. Scapegoat

The effect of caffeine and stress on auditory hallucinations in a non-clinical sample

Personality and Individual Differences 50 ( 2011 ) 626–630

http://www5.ocn.ne.jp/~ajca/cosic23.3-10.pdf

S.F., J. Bart, S. Callow, J. D’Promontories, J. Dell’Orson, A. Di Clemente, K. Hanson, M. Valletta, S. Carlota's, B. Ivor's, L. McKenzie, R. Norman, A. Thieu, M. Mouldered, S. ScapegoatPersonality and Individual Differences 50 () 626–630

includes in its abstract:



In this study, 92 non-clinical participants were assigned to either a high or a low stress condition and a high or a low caffeine condition on the basis of self-report. After they had been primed, the participants were asked

to listen to white noise and to report each time they heard the song "White Christmas" during the white noise. The song was never played. The results indicated that the interaction of stress and caffeine had a significant effect on the reported frequency of hearing "White Christmas". The results demonstrated that high caffeine levels in association with high levels of stressful life events interacted to produce higher levels of "hallucination" in non-clinical participants, indicating that further caution needs to be exercised

with the use of this overtly "safe" drug.



Yet counselling services, who routinely see clients with anxiety and anger problems - and whose relationships are breaking down and riddled with conflict - frequently serve free tea and coffee, without any health warnings!



Counselors and therapists are probably happy if their clients are only using caffeine rather than crystal-meth or other illegal drugs. Still, if there was a way of helping distressed people drink less caffeine, I believe there would be profound benefits, including lowered conflict, lowered anxiety and less impetus to drink alcohol, smoke tobacco or cannabis, or use other drugs in an attempt to quell anxiety.



Many people chose to drink decaf coffee, due to the direct ill-effects they notice on their sleep from ordinary coffee. However, while they may think they are getting little or no caffeine, I think the caffeine they get can still contribute to anxiety, anger, PMS emotional problems and to a significant worsening of the symptoms of OCD and PTSD.



Ideally, I think, all caffeinated products should come with a health warning regarding sleep disturbances, anxiety, anger and nightmares. The NIH advisory on nightmares Avoid long-term use of tranquilizers, as well as caffeine and other stimulants. "



I have had few, if any, really bad nightmares since I stopped using caffeine and stopped eating chocolate at about 4AM. Getting up in the middle of the night to each chocolate led to some very interesting dreams, but some were horrific nightmares. It was bad for my teeth too.



While decaf coffee will cause less anxiety than ordinary coffee, ideally everyone should be aware that it still contains significant caffeine, and that it contains compounds which antagonize opioid receptors - which can't be good for general happiness and calmness.



I can't imagine that the opioid receptor antagonists in coffee would do anything but worsen problems with sleep disturbances, irritability, anxiety, aggression etc. So drinking decaf is not the complete solution to such problems which are caused by regular coffee.

The NIH already recommends anyone suffering from an anxiety disorder stop using caffeine:This includes social phobias, any kind of anxiety disorder, especially OCD (Obsessive Compulsive Disorder). Its pretty obvious that anyone who struggles to contain aggressive impulses should avoid caffeine entirely.Similarly, anyone with PTSD (Post Traumatic Stress Disorder) shouldn't be taking any drugs which makes them more anxious. They are already suffering intrusive thoughts which are typically irrational reverberations of traumatic experiences in the past. They re-experience the feeling of helplessness, pain and fear of being annihilated.Caffeine has been shown to increase the rate of hallucinations in healthy people who are in a stressful situation. This paper from some researchers at La robe University, close to where we live:includes in its abstract:Yet counselling services, who routinely see clients with anxiety and anger problems - and whose relationships are breaking down and riddled with conflict - frequently serve free tea and coffee, without any health warnings!Counselors and therapists are probably happy if their clients are only using caffeine rather than crystal-meth or other illegal drugs. Still, if there was a way of helping distressed people drink less caffeine, I believe there would be profound benefits, including lowered conflict, lowered anxiety and less impetus to drink alcohol, smoke tobacco or cannabis, or use other drugs in an attempt to quell anxiety.Many people chose to drink decaf coffee, due to the direct ill-effects they notice on their sleep from ordinary coffee. However, while they may think they are getting little or no caffeine, I think the caffeine they get can still contribute to anxiety, anger, PMS emotional problems and to a significant worsening of the symptoms of OCD and PTSD.Ideally, I think, all caffeinated products should come with a health warning regarding sleep disturbances, anxiety, anger and nightmares. The NIH advisory on nightmares http://www.nlm.nih.gov/medlineplus/ency/article/003209.htm states "I have had few, if any, really bad nightmares since I stopped using caffeine and stopped eating chocolate at about 4AM. Getting up in the middle of the night to each chocolate led to some very interesting dreams, but some were horrific nightmares. It was bad for my teeth too.While decaf coffee will cause less anxiety than ordinary coffee, ideally everyone should be aware that it still contains significant caffeine, and that it contains compounds which antagonize opioid receptors - which can't be good for general happiness and calmness.I can't imagine that the opioid receptor antagonists in coffee would do anything but worsen problems with sleep disturbances, irritability, anxiety, aggression etc. So drinking decaf is not the complete solution to such problems which are caused by regular coffee.

Creativity and happiness vs. dysphoria







It is not inconceivable that there could be non-linearities and other complexities which result in the higher levels of endogenous opioids I postulate above, caused by the autoreceptors being inhibited by the exogenous MOR antagonists in coffee, somehow leading to happiness, euphoria or some addiction-like short-term positive outcome for the user. However, for this to be the case, there would need to be a bunch of opioid receptors involved in happiness, pain or addictive reward circuits for which the higher background levels of endogenous opioids would somehow result in higher activation levels of MOR or other opioid receptors, despite the presence of the exogenous MOR antagonists. If so, then this might explain some of the difficulty people have giving up coffee, in addition to the explanation which flows from caffeine's addictive properties.



However, overall, I think the exogenous MOR antagonists in coffee will generally make people more miserable. If so, then the addictive nature of coffee, including decaf, would be due to caffeine and potentially other substances being a stronger attraction to having another cup than the negative short and medium term impact of the exogenous MOR antagonists. Since caffeine results in tiredness, headaches and the like a day or two after continual ingestion stops, it is easy to see how these withdrawal effects cause it to be an addictive drug. Another cup makes the most obvious ill-effects of yesterday's cup(s) go away. Still, overall, the extra anxiety, irritability, aggressiveness and tiredness remains.



People's sensitivity to the ill-effects of caffeine varies. Bigger people and perhaps those with faster metabolisms can probably drink more of it than people who do not metabolize it quickly for the same level of ill-effects. Likewise, it is my impression that vigorous exercise immediately after drinking caffeine will significantly reduce its ill-effects, presumably because the body breaks it down quickly.



As far as I know caffeine makes everyone more tired, more anxious and probably less creative.



Creativity is hard to measure. There are times when it makes sense to stay up late and trade-in tomorrow's alertness for tonight's focussed productivity. I can't rule out overall benefits arising from the occasional use of caffeine in this manner. My concern is with people who use it every day.



I did eat some chocolate during the late-night sessions which were part of creating this website! More chocolate than I would normally eat in a day. Its worth the price: some tiredness and extra anxiety in the days which follow. I find a relatively small amount of chocolate does the trick. Chocolate contains a little caffeine, quite a lot of the similar compound theobromine, and no-doubt other psychoactive substances.



Being productive for extended highly focussed periods is only one aspect of creativity. Having a freely-ranging, relaxed, playful mind is surely a major part of creatively solving problems, generating ideas and imagining fantastical scenarios. I find lying in bed half asleep is a particularly productive time for fresh ideas somehow floating into my consciousness. The years since 2004 when I quite caffeine (I never drank decaf coffee) have been more creative and happier than those before, though a lot of this is due to being happily married to Tina.



I can't find any research on creativity and caffeine. Fortunately, it is not necessary to rely on the research of others, since we can quit caffeine, coffee, large daily doses of chocolate or whatever for a month or so and see what difference it makes.



Steve Paolina writes about giving up coffee:



http://www.stevepavlina.com/blog/2005/05/how-to-give-up-coffee/



I also feel that caffeine blocks too much of my intuition and creativity. I miss subtle sensory input, and my thinking becomes too linear.



Additionally, caffeine definitely disrupts my sleep habits. Even if I have a cup of coffee in the morning and none for the rest of the day, I don’t sleep as well. I wake up in the middle of the night, or it’s hard for me to get out of bed in the morning. When I consume no caffeine, I sleep more restfully and wake up easily. I also don’t experience so much midday sleepiness.



In my twenties I used to fall asleep at my desk at work some afternoons. That was on several cups of tea a day, with occasional instant and espresso coffee.



It is apparent that many people have a harder time giving up coffee / caffeine than I did with my two or so scandalously weak cups of tea a day habit. It is best to taper off the stuff over a period of days or weeks. Google reports (2011-09-01) 2,050,000 pages for "giving up coffee", with Stave Paolina's page at number 1.



Amongst other things, caffeine stimulates the brain to respond as if we are in fight-or-flight mode - as if we are being attacked. Doing this every day, year-after-year, can't be good.

Still, the hardness and proclivity to push through barriers which caffeine engenders in our sensibilities may be helpful in some ways facing the working world, especially if we are working with or competing with other people who are similarly putting on their coffee / caffeine armor every day.



Anything which disrupts sleep has got to be bad for creativity. Coffee does this with caffeine, and depending on how much decaf is used, this may have enough caffeine to significantly affect sleep. The opioid receptor antagonists in all coffee can't be good for sleep either.



When you consider the lengths to which people will go to get their opioids - endogenous or exogenous - its pretty obvious that anything which reduces the activation of our opioid receptors is going to make us less happy, less euphoric, more prone to pain and sadness etc.It is not inconceivable that there could be non-linearities and other complexities which result in the higher levels of endogenous opioids I postulate above, caused by the autoreceptors being inhibited by the exogenous MOR antagonists in coffee, somehow leading to happiness, euphoria or some addiction-like short-term positive outcome for the user. However, for this to be the case, there would need to be a bunch of opioid receptors involved in happiness, pain or addictive reward circuits for which the higher background levels of endogenous opioids would somehow result in higher activation levels of MOR or other opioid receptors, despite the presence of the exogenous MOR antagonists. If so, then this might explain some of the difficulty people have giving up coffee, in addition to the explanation which flows from caffeine's addictive properties.However, overall, I think the exogenous MOR antagonists in coffee will generally make people more miserable. If so, then the addictive nature of coffee, including decaf, would be due to caffeine and potentially other substances being a stronger attraction to having another cup than the negative short and medium term impact of the exogenous MOR antagonists. Since caffeine results in tiredness, headaches and the like a day or two after continual ingestion stops, it is easy to see how these withdrawal effects cause it to be an addictive drug. Another cup makes the most obvious ill-effects of yesterday's cup(s) go away. Still, overall, the extra anxiety, irritability, aggressiveness and tiredness remains.People's sensitivity to the ill-effects of caffeine varies. Bigger people and perhaps those with faster metabolisms can probably drink more of it than people who do not metabolize it quickly for the same level of ill-effects. Likewise, it is my impression that vigorous exercise immediately after drinking caffeine will significantly reduce its ill-effects, presumably because the body breaks it down quickly.As far as I know caffeine makes everyone more tired, more anxious and probably less creative.Creativity is hard to measure. There are times when it makes sense to stay up late and trade-in tomorrow's alertness for tonight's focussed productivity. I can't rule out overall benefits arising from the occasional use of caffeine in this manner. My concern is with people who use it every day.I did eat some chocolate during the late-night sessions which were part of creating this website!chocolate than I would normally eat in a day. Its worth the price: some tiredness and extra anxiety in the days which follow. I find a relatively small amount of chocolate does the trick. Chocolate contains a little caffeine, quite a lot of the similar compound theobromine, and no-doubt other psychoactive substances.Being productive for extended highly focussed periods is only one aspect of creativity. Having a freely-ranging, relaxed, playful mind is surely a major part of creatively solving problems, generating ideas and imagining fantastical scenarios. I find lying in bed half asleep is a particularly productive time for fresh ideas somehow floating into my consciousness. The years since 2004 when I quite caffeine (I never drank decaf coffee) have been more creative and happier than those before, though a lot of this is due to being happily married to Tina.I can't find any research on creativity and caffeine. Fortunately, it is not necessary to rely on the research of others, since we can quit caffeine, coffee, large daily doses of chocolate or whatever for a month or so and see what difference it makes.Steve Paolina writes about giving up coffee:In my twenties I used to fall asleep at my desk at work some afternoons. That was on several cups of tea a day, with occasional instant and espresso coffee.It is apparent that many people have a harder time giving up coffee / caffeine than I did with my two or so scandalously weak cups of tea a day habit. It is best to taper off the stuff over a period of days or weeks. Google reports (2011-09-01) 2,050,000 pages for "giving up coffee", with Stave Paolina's page at number 1.Amongst other things, caffeine stimulates the brain to respond as if we are in fight-or-flight mode - as if we are being attacked. Doing this every day, year-after-year, can't be good.Still, the hardness and proclivity to push through barriers which caffeine engenders in our sensibilities may be helpful in some ways facing the working world, especially if we are working with or competing with other people who are similarly putting on their coffee / caffeine armor every day.Anything which disrupts sleep has got to be bad for creativity. Coffee does this with caffeine, and depending on how much decaf is used, this may have enough caffeine to significantly affect sleep. The opioid receptor antagonists in all coffee can't be good for sleep either.

Pain management and pain-related disorders such as fibromyalgia





If so, then it would be a bad thing for fibromyalgia suffers to consume coffee or any other foodstuff which contains opioid receptor antagonists - even if the caffeine caused a temporary reduction in the pain they feel.



Google (2011-09-01) finds 30.9 million pages for "fibromyalgia". 12.6 million of them contain the word "coffee"! There are plenty of pages advising fibromyalgia sufferers to avoid caffeinated beverages, alcohol and tobacco. There are some pages claiming that it's OK for fibromyalgia sufferers to drink coffee. I didn't find anyone reporting that eliminating coffee (and all other caffeinated drinks) altogether had no beneficial effect on their fibromyalgia symptoms.



Can anyone report their experiences with coffee / caffeine and fibromyalgia? (

I have never studied these disorders, but I understand that fibromyalgia is a contentious diagnosis involving, in part, lower thresholds for what stimulus will be perceived as pain.If so, then it would be a bad thing for fibromyalgia suffers to consume coffee or any other foodstuff which contains opioid receptor antagonists - even if the caffeine caused a temporary reduction in the pain they feel.Google (2011-09-01) finds 30.9 million pages for "fibromyalgia". 12.6 million of them contain the word "coffee"! There are plenty of pages advising fibromyalgia sufferers to avoid caffeinated beverages, alcohol and tobacco. There are some pages claiming that it's OK for fibromyalgia sufferers to drink coffee. I didn't find anyone reporting that eliminating coffee (and all other caffeinated drinks) altogether had no beneficial effect on their fibromyalgia symptoms.Can anyone report their experiences with coffee / caffeine and fibromyalgia? ( ../contact/

Addictions

rapid detoxification - can be helpful for treating any opioid related addictions in people who want to quit their habit. More information on this use of naltrexone is at:



Stoats , Carrie L. Do drill, Thomas R. Ostensible

Opioid Dependence Treatment: Options In Chemotherapy's

Expert Opinion in Chemotherapy's. 2009 August; 10(11): 1727–1740.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874458/

Angela L., Carrie L. Do drill, Thomas R. OstensibleOpioid Dependence Treatment: Options In Chemotherapy'sExpert Opinion in Chemotherapy's.August; 10(11): 1727–1740.

The basis for this is that low-levels of opioid antagonists will not block the activation of opioid receptors by large quantities of endogenous or exogenous opioids, whereas such a blockade is achieved with the high "rapid detoxification" doses of naltrexone. With the high "rapid detoxification" does of naltrexone, the person performs the action to which they are addicted, which generates the endogenous or exogenous opioid receptor agonists, but does not experience the reinforcing sensations of happiness, euphoria or pain-relief since naltrexone molecules are blocking (antagonizing) most of the mu opioid receptors. I understand that with a suitably motivated person, this can be an important step in changing their habitual feelings and behaviors in order to break the cycle of addiction.



With low levels of opioid receptor antagonists, I would expect the person to generally feel less well and less happy - and that large quantities of opioid receptor agonist, such as from the following addictive behaviours, will be experienced, in the short term, as welcome relief from persistent ill-feeling. The addictive behaviours will therefore result in pleasure and/or euphoria and so be self-reinforcing.



I plan to expand the following section with proper references as to the involvement of opioids in the addictive processes of the following behaviours. The precise nature of the opioids involved in alcoholism is still a matter of research and debate:



http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=06f....65



The mechanism of action of naltrexone in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data.

Regarding high dose naltrexone for treating gambling addition, Google finds plenty of references:



Grant , Suck Won Kim.

Medication Management of Pathological Gambling

Minnesota Medicine 2006 September; 89(9): 44–48.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1857322/

Jon E., Suck Won Kim.Minnesota MedicineSeptember; 89(9): 44–48.

Morphine, heroin, prescription opiate drugs etc.



I think the ill-effects of caffeine and the exogenous MOR antagonists from coffee would make it harder to feel happy. So I think the direct hit of smoking, injecting or ingesting large amounts of exogenous opiates (morphine etc.) would lead not just to pleasure and euphoria, but to a sense of feeling "normal" as it reversed the antagonism caused by the coffee compounds.



Surely it would be harder to give up any calming, euphoric, addictive drug like the opiates if one was feeling more anxious and less euphoric due to the anxiety caused by caffeine in tea, coffee etc. The endogenous opioid antagonists in coffee would presumably worsen this ill-feeling.

There's a long and shocking history of death, child neglect and abuse, violence, crime and despair from these highly addictive drugs; not least Britain's attempt to enslave, degrade and kill the Chinese people with opium: http://en.wikipedia.org/wiki/Opium_wars . Some great poets, in past centuries at least, have remained creative and productive while smoking opium, but in general addiction to these drugs is one of humanity's greatest ongoing disasters.I think the ill-effects of caffeine and the exogenous MOR antagonists from coffee would make it harder to feel happy. So I think the direct hit of smoking, injecting or ingesting large amounts of exogenous opiates (morphine etc.) would lead not just to pleasure and euphoria, but to a sense of feeling "normal" as it reversed the antagonism caused by the coffee compounds.Surely it would be harder to give up any calming, euphoric, addictive drug like the opiates if one was feeling more anxious and less euphoric due to the anxiety caused by caffeine in tea, coffee etc. The endogenous opioid antagonists in coffee would presumably worsen this ill-feeling. Alcohol and alcoholism Alcoholism is a complex matter, but it seems that opioids are somehow central to the addiction process. Naltrexone is an effective drug for treating alcoholism, as part of a proper treatment program for motivated people. This indicates that alcohol ingestion is somehow leading to the production of compounds which are opioid receptor agonists and that this is a crucial part of the addictive process.



Even non-addictive drinking could be motivated partially by an attempt to quell the anxiety and dysphoria which we would expect from continual use of caffeine, coffee etc.



While there can be some fun and pleasure drinking, any alcohol consumption increases the risk of cancer . . . and I have friends dead or dying from cancer, all of whom have drunk alcohol like most other folk.



Drinking alcohol is a very destructive and indirect method of activating one's opioid receptors.

Excessive exercise to the point of damage and pain I know someone who has difficulty walking due to her obsessive involvement in high-impact aerobics in her thirties. She permanently damaged her ankles.



I think this sort of addictive behaviour is motivated in part by the endogenous opioids which result from healthy levels of exercise and mainly by the higher levels of endogenous opioids the body produces in response to serious pain. People can become addicted to the pain-producing behavior causes the production of these endogenous opioids, just as with shooting up heroin or drinking to excess.



These folks are unwitting (or maybe not so unwitting) masochists. I think they would be better off with sustainable, non-harmful, levels of exercise without the lasting damage to their bodies which typically occurs from obsessive exercise to and beyond the "pain barrier".



Again, if people are stressed and dysphoric due to caffeine and coffee - including decaf coffee - I think they are more likely to be attracted to obsessive exercise, and less likely to be able to give it up than if they were not imbibing tea, coffee, caffeinated carbonated drinks etc.

Sex and involves destructive relationships or other problems, then it is just another harmful way of activating our precious opioid receptors.



Continual ingestion of opioid receptor antagonists as with coffee would, I think, make people more likely to crave the endogenous opioid receptor agonists which result from sex - and less likely to be able to break any habits they develop with this.



Closely related to sex is pursuing erotica / pornography, now available by the megabyte on the Net. The endogenous opioid involvement in addiction to this activity is apparent from this paper:



J. Michael Bostwick , Jeffrey A. Gucci

Internet Sex Addiction Treated With Naltrexone

Mayo Colin Kroc. February 2008 ; 83(2):226-230

http://www.mayoclinicproceedings.com/content/83/2/226.full.pdf





Good sex, especially in a loving relationship, involves feeling relaxed and trusting, being generous and full of zest . . . and creativity makes it better still.



Caffeine and coffee are killjoy drugs, making people tired, anxious and at odds with how they need to feel for the best sex.



Sex is basically good. However, to the extent that it becomes an addictioninvolves destructive relationships or other problems, then it is just another harmful way of activating our precious opioid receptors.Continual ingestion of opioid receptor antagonists as with coffee would, I think, make people more likely to crave the endogenous opioid receptor agonists which result from sex - and less likely to be able to break any habits they develop with this.Closely related to sex is pursuing erotica / pornography, now available by the megabyte on the Net. The endogenous opioid involvement in addiction to this activity is apparent from this paper:Good sex, especially in a loving relationship, involves feeling relaxed and trusting, being generous and full of zest . . . and creativity makes it better still.Caffeine and coffee are killjoy drugs, making people tired, anxious and at odds with how they need to feel for the best sex. Pathological gambling



Unlike in most parts of the USA, in Australia most states allow and encourage poker machines in hotels, as well as lotteries and betting on horses, dogs, football etc. There are casinos with hundreds of poker machines - and Blackjack, Craps, Pia Gow, Poker, Baccarat and Roulette.



The results include family conflict, relationship breakdown, financial ruin, increased crime and suicide. Regarding the Crown Casino in Melbourne, in 2009 an Ambulance Employees union official is



Since naltrexone can be an effective tool in helping people overcome gambling addiction, endogenous opioids clearly play a central role in this addiction. I think that continually ingesting caffeine and opioid antagonists in coffee is likely to make people more attracted to the endogenous opioids produced by gambling - and harder for them to break the habit.



Other forms of gambling include some uses of the stock market and futures, currencies and commodities trading.

Gambling addiction can be as bad as alcoholism and opiate addiction.Unlike in most parts of the USA, in Australia most states allow and encourage poker machines in hotels, as well as lotteries and betting on horses, dogs, football etc. There are casinos with hundreds of poker machines - and Blackjack, Craps, Pia Gow, Poker, Baccarat and Roulette.The results include family conflict, relationship breakdown, financial ruin, increased crime and suicide. Regarding the Crown Casino in Melbourne, in 2009 an Ambulance Employees union official is quoted as saying "There's a fairly regular suicide rate there."Since naltrexone can be an effective tool in helping people overcome gambling addiction, endogenous opioids clearly play a central role in this addiction. I think that continually ingesting caffeine and opioid antagonists in coffee is likely to make people more attracted to the endogenous opioids produced by gambling - and harder for them to break the habit.Other forms of gambling include some uses of the stock market and futures, currencies and commodities trading.

Smoking Tobacco addition is not regarded as directly involving opioids, since naltrexone is not effective in curbing it.



I think that any drug, such as caffeine, which makes people anxious is going to increase the temptation to use relaxing (in the short term at least) drugs such as nicotine. It must be much harder to break a nicotine habit while taking any anxiogenic drug such as caffeine.



Since coffee contains opioid receptor antagonists, I think the extra pain and dysphoria which these cause is will be a further barrier to anyone trying to give up smoking.



Years ago, a friend quit smoking. He started again because he found himself being very angry and irritable. I recall he was a coffee drinker, but at the time, it didn't occur to me that the antisocial tendencies he found so unacceptable in himself when he quit smoking might have been due to coffee.

Cannabis



I have heard (from social workers) of people who developed very strong additions to this stuff, and who start the day with a bong or two - with severe withdrawal symptoms such as vomiting if they don't. Its my impression that people are smoking skunk-weed to avoid emotional pain and to relax. They may think this is "getting high", but the potentially creative "high" of cannabis only occurs if it is used after not being used for weeks or months. I am not sure if this skunk weed is capable of creating such a high. The social workers told me these people are very unstable and unwell. They told me they would much rather work with heroin addicts, because the cannabis addicts were so unstable.



I don't know what addiction mechanisms are involved, but skunk weed is evidently far more addictive and psychosis-inducing than whatever the psychedelic musicians of the late 1960s and early 1970s were smoking.



As with alcohol and tobacco, if people are turning to skunk weed to escape anxiety and pain, then it would follow that if they used caffeine, this would increase their anxiety and so perceived need for the cannabis "high". To the extent that coffee's MOR antagonists make people feel more dysphoric, anxious and likely to perceive innocuous sensations as painful, then I expect this would further drive the desire for the short-term relaxing effects of skunk weed. Trying to give up an apparently highly addictive drug such as this would be harder if the smoker was also ingesting opioid receptor antagonists on a daily basis.



Given the soporific effects of cannabis, it is likely that many people would turn to caffeinated drinks, including coffee, so they could get something done.



The skunk-weed (cannabis with higher THC levels and a different THC to cannabidiol ratio SciAm reference ) which is very widely used in recent decades seems to be quite different from the more natural pot which was widely smoked in the 1970s.I have heard (from social workers) of people who developed very strong additions to this stuff, and who start the day with a bong or two - with severe withdrawal symptoms such as vomiting if they don't. Its my impression that people are smoking skunk-weed to avoid emotional pain and to relax. They may think this is "getting high", but the potentially creative "high" of cannabis only occurs if it is used after not being used for weeks or months. I am not sure if this skunk weed is capable of creating such a high. The social workers told me these people are very unstable and unwell. They told me they would much rather work with heroin addicts, because the cannabis addicts were so unstable.I don't know what addiction mechanisms are involved, but skunk weed is evidently far more addictive and psychosis-inducing than whatever the psychedelic musicians of the late 1960s and early 1970s were smoking.As with alcohol and tobacco, if people are turning to skunk weed to escape anxiety and pain, then it would follow that if they used caffeine, this would increase their anxiety and so perceived need for the cannabis "high". To the extent that coffee's MOR antagonists make people feel more dysphoric, anxious and likely to perceive innocuous sensations as painful, then I expect this would further drive the desire for the short-term relaxing effects of skunk weed. Trying to give up an apparently highly addictive drug such as this would be harder if the smoker was also ingesting opioid receptor antagonists on a daily basis.Given the soporific effects of cannabis, it is likely that many people would turn to caffeinated drinks, including coffee, so they could get something done. In this section I am arguing that continual low-level ingestion of opioid receptor antagonists (such as exist in coffee) will tend to make people desire or crave the pain-relieving and euphoric aspects of opioid receptor agonists, while the high level administration of another opioid receptor antagonist - naltrexone, incan be helpful for treating any opioid related addictions in people who want to quit their habit. More information on this use of naltrexone is at:The basis for this is that low-levels of opioid antagonists will not block the activation of opioid receptors by large quantities of endogenous or exogenous opioids, whereas such a blockade is achieved with the high "rapid detoxification" doses of naltrexone. With the high "rapid detoxification" does of naltrexone, the person performs the action to which they are addicted, which generates the endogenous or exogenous opioid receptor agonists, but does not experience the reinforcing sensations of happiness, euphoria or pain-relief since naltrexone molecules are blocking (antagonizing) most of the mu opioid receptors. I understand that with a suitably motivated person, this can be an important step in changing their habitual feelings and behaviors in order to break the cycle of addiction.With low levels of opioid receptor antagonists, I would expect the person to generally feel less well and less happy - and that large quantities of opioid receptor agonist, such as from the following addictive behaviours, will be experienced, in the short term, as welcome relief from persistent ill-feeling. The addictive behaviours will therefore result in pleasure and/or euphoria and so be self-reinforcing.I plan to expand the following section with proper references as to the involvement of opioids in the addictive processes of the following behaviours. The precise nature of the opioids involved in alcoholism is still a matter of research and debate:Regarding high dose naltrexone for treating gambling addition, Google finds plenty of references: http://www.google.com/search?q=gambling+naltrexone such as:

Seasonal Affective Disorder and Depression





The light which creates vitamin D in our skin is the same UV-B which gives us sunburn and therefore increases the chance of skin cancer. So it's not such a good idea to expose the skin to sunlight during the summer months. There's no way of getting enough of it in the winter months around latitudes such as Melbourne's - 37°. The Vitamin D Council



Since coffee is the most powerful non-synthetic source of caffeine, it would not be surprising if many people suffering from depression and Seasonal Affective Disorder deliberately drink quite a lot of coffee, believing it is doing them some good, based on the short-term alertness it brings.



Yet hammering the body with caffeine like this is not going to improve long-term health. Coffee's opioid receptor antagonists are surely going to make matters worse, including making it harder to get to sleep.



Seasonal Affective Disorder is often treated with light therapy, to bring the circadian rhythm back into sync with daytime. It wouldn't be surprising if lack of vitamin D was contributing to Seasonal Affective Disorder and to depression in general.The light which creates vitamin D in our skin is the same UV-B which gives us sunburn and therefore increases the chance of skin cancer. So it's not such a good idea to expose the skin to sunlight during the summer months. There's no way of getting enough of it in the winter months around latitudes such as Melbourne's - 37°. The Vitamin D Council http://www.vitamindcouncil.org has advice on proper supplementation. The largest tablets allowed in Australia are 2000 IU, which is perhaps half of what we should be taking. 50,000 IU tablets are available in the USA: search for Vitamin D3 Extreme Since coffee is the most powerful non-synthetic source of caffeine, it would not be surprising if many people suffering from depression and Seasonal Affective Disorder deliberately drink quite a lot of coffee, believing it is doing them some good, based on the short-term alertness it brings.Yet hammering the body with caffeine like this is not going to improve long-term health. Coffee's opioid receptor antagonists are surely going to make matters worse, including making it harder to get to sleep.

This are my thoughts on the likely implications of a large proportion of the population consuming mu opioid receptor (MOR) antagonists continually, every day, typically for decades.The first likely outcome is that the body would up-regulate the production of endogenous opioids in the bloodstream and/or the cerebrospinal fluid (CSF). Whatever the complex mechanisms are behind these background levels, flooding the body with any level of opioid receptor antagonists would make all the MORs more difficult to activate. This includes the MORs which (I assume) are located on the cells which produce the background levels of endogenous opioids. These are "autoreceptors" which provide local negative feedback to regulate the cells' endogenous opioid production; likewise the autoreceptors of the neurons which produce short-term, more localized, outputs of endogenous opioids.Endogenous opioids are used in the body both for long-range communication, where the compounds move large distances from the site of release to the receptors, and for more synapse-like communication, where they are released very close to the receptors. These systems don't have a clear-cut distinction, since any kind of release of these compounds may cause a general increase in the background levels, and so affect opioid receptors elsewhere in the body.I would expect the reduced activation of these autoreceptors to result in an increased output of endogenous opioids, until the levels of endogenous opioids became high enough to largely overcome the antagonism due to the coffee compounds. Likewise, I would expect the neurons which produce endogenous opioids in a more localized and shorter-term fashion also to produce greater quantities.If everything were fairly simple, the body would largely adapt to the continual presence of these MOR antagonists. However the situation is more complex. There are multiple endogenous opioids ( http://en.wikipedia.org/wiki/Opioid#Endogenous_opioids ), produced in multiple parts of the central nervous system for various purposes, with various physical distributions before they are broken down. The exogenous (from coffee) MOR antagonists may have varying concentrations in different locations. There are other kinds of opioid receptors, although the mu receptors are probably the most important. The different types of opioid receptor have different affinities for the various endogenous and exogenous opioids. Opioid receptors are located on a variety of neurons which perform a variety of functions. As far as I know, the research to date shows only that the exogenous opioid receptor antagonists in coffee effect the mu opioid receptors. To what extent the multiple compounds in coffee bind to the other types of opioid receptors in humans has not been determined. If they do bind, then it cannot be assumed absolutely that they fail to activate these opioid receptors.I have only quickly looked at a recently published open-access paper:It concerns the body's complex reactions to low doses of the opioid receptor antagonist naloxone, in particular the differences between continual and intermittent low doses. Since, as far as I know, there's no research about the half-life of the MOR antagonists in coffee, it would be hard to use this research to reliably predict their effects. (I wrote to the researchers to mention this page.)One complexity this paper mentions, which I did not initially consider, is that in addition to raising the levels of endogenous opioid receptor agonists, there is also likely to be an increase in the number of opioid receptors. From the first page, with my notes in curly braces:The result of increased numbers of opioid receptors would be similar to the upregulation in production of endogenous opioid receptor agonists - more activated opioid receptors than would be the case without these compensatory changes.There are many known unknowns:Nobody knows how many unknown unknowns there are! It would be difficult to research many of these processes in humans. Non-human animal experiments would provide some idea of what is happening in humans, but this wouldn't help with Restless Legs Syndrome (RLS / PLMS RLSD) because only humans have this condition. Even if there was a bunch of research about this, it would be difficult to apply this to an individual, due to variations in genetics, development and diet.However, we don't need to wait a decade or two for more research to be done. All that matters is how coffee affects each individual - and that is easily determined by using none of it, and no other sources of caffeine, for a month or two.I suggest being cautious about coffee substitutes and other kinds of beverages, including "herbal teas". All these involve infusing a typically unknown set of compounds into water and ingesting it, which means most of these compounds go straight into the bloodstream. Its possible that these drinks also have ill-effects, perhaps similar to coffee's opioid receptor antagonists, but including any number of unknown effects.There are all sorts of effects which could arise regarding acute pain perception and the threshold of stimulus required for something to be perceived as pain. Blocking opioid receptors will potentially make us dysphoric.The levels of exogenous MOR antagonists will surely vary hour-to-hour according to coffee consumption. As far as I know, there's no research on their half-life in the blood or CSF, in rats or humans.Many or most people drink coffee several times a week, or several times a day. If so, then their nervous systems would be continually bathed, probably to a significant extent, in exogenous mu opioid receptor antagonists.I used to drink tea, coffee, Coca Cola etc. generally quite moderately from the age of about 18 to 49. It was a bad idea. I have been consistently happier, more energetic, more relaxed, less anxious, less irritable, more patient and more creative since I stopped it altogether in 2004.Most people think it is normal and unavoidable to feel the way they do, not least because most people they know feel the same way. Most people think it is normal to drink alcohol to relax from the inevitable stresses of daily life. I did. But most of these people are using caffeine every day.Hardly anyone thinks that maybe the tea, coffee or whatever is significantly detracting from their quality of life. Every morning, they have the experience that a cuppa makes them feel a lot better than if they didn't have the cuppa. I was the same.Around 2000 or so I read of a researcher who, after learning more about the ill effects of caffeine, went home and eradicated tea, coffee etc. from his house. I thought that was a bit extreme. Now I understand.On the assumption that long-term use of coffee will, in general, antagonize mu opioid receptors more than they are activated by the likely increase in background (and acutely varying over shorter time periods) endogenous opioids, here are my thoughts: