I am all onboard with the "need for sleep". Slept for 10 hours this Saturday and could not be happier.
But in many ways, good sleep, important as it is, is kind of like "good love life". Is it important to have "good love life"? You bet! But it is not easy to have "good love life" even if one decides to have it -- it is hard to get.
Sleep is also like this, so many commitments, BS etc. I have to wake up at 5:45am during the week days. Even though I love my job, I hate waking up at 5:45. Even though I own my business I cannot change this. Now as for going to bed early, I often start writing something in the evening, or read stuff like your substack etc. Cannot go to bed at 9pm.
Not so easy to have good sleep, even though it is 100% extremely important!!
Anyway, knowing what you wrote, I will try harder!
It's definitely true that modern life and work has made it difficult for many to get good night's rest. The main problem is that the body doesn't quite give a crap how much work we have. Our body just wants to tell us, "hey, get sleep now or you'll regret it later!" As much as we would like to tell it to not react so negatively.
It should kind of remind us that modernity can't get away from our biological processes that have been cultivated over hundreds of thousands of years.
😄 I don't need a reminder. I get 8 hours every night unless I'm keeping myself up too late, which happens every once in awhile. This is what the good reminder is about, that I get into bed by 10:00 every night! Do you get good sleep regularly?
Great caption on sleep. And what interferes with it? Some of our cherished habits, like caffeine, and looking at this little screen in my hand or on my desk within a couple hours before going to bed.
Sleep is one of the low hanging fruits we can do for improving our health. I mean, I can exercise, I can take all the pills for anti-inflammatory, immune support, etc, but if I don't get my sleep, they aren't doing me that much good.
It's so easy to improve sleep, yet for as much outcry as we have over everything else going on so many people just don't seem to alert others to the need to get good sleep. It's probably one of the best things you can do for your own health!
Alcohol is a sleep disruptor. So are many SSRI "antidepressants".
Caffeine is a terrible sleep disruptor, not just through its immediate effects a few hours after consuming it. Caffeine drives Restless Legs Syndrome / Periodic Limb Movement Disorder (RLS / PLMD, which are separate diagnostic criteria - sensation and movement - for the one underlying disorder). I didn't know this when I wrote a Letter about this https://www.liebertpub.com/doi/abs/10.1089/jcr.2014.0024 . I should make an updated version of this publicly available. There is an article from about 15 years ago I can't find right now which reports on people with RLS/PLMD whose problems went away after they stopped using caffeine.
It is my impression that caffeine withdrawal drives RLS/PLMD - the effects of consuming caffeine more than 3 hours or so beforehand. A small amount of caffeine may quell these withdrawal effects and so reduce RLS/PLMD for a while.
Chocolate contains caffeine, theobromine (which very similar to caffeine, and from which coffee plants make their caffeine) and other substances. Unfortunately there is something in chocolate which drives RLS/PLMD immediately and in the ~~3 to 6 hours which follow.
Coffee, but not tea or chocolate, contains opioid receptor antagonists. These surely directly disrupt sleep by reducing the level of background opioid receptor activation caused by endogenous opioids. See the research cited at: https://aminotheory.com/coffee/ . Opioid receptor antagonists also directly drive RLS/PLMD.
RLS/PLMD is a severe sleep disruptor - but I believe that the same processes, at a level which would not meet RLS/PLMD diagnostic criteria, are a powerful sleep disruptor too. I am sure this is very common, and that it is classified as idiopathic (no known cause) insomnia. I speak from personal experience. Actual RLS is noticeable disturbed sensations. Actual PLMD is toes and foot lifting up, and perhaps whole leg withdrawal reflex responses. Below this level, there can be a subtle but significant level of disturbance - it is difficult to get "comfortable" - which disrupts sleep.
The etiology of RLS/PLMD is officially unknown, though it is well known that shortage of iron drives it. This is easily understood in terms of iron being a co-factor for the tyrosine hydroxylase enzyme. This converts the common amino acid tyrosine into L-DOPA, which is then converted by another enzyme (which can usually be relied upon to work well) into dopamine. This occurs in the output terminals (axons) of neurons with the dopamine being stored in vacuoles, from which it is released into the synaptic cleft as a (typically inhibitory) neurotransmitter when the neuron fires.
Dopamine receptor agonists (which activate the receptor) and opioid receptor agonists (AKA exogenous opioids and those produced endogenously in the body) are well known to quell RLS/PLMD. Opioid drugs are highly addictive and debilitating - but are used for RLS when nothing else works. Dopamine receptor agonist drugs work for a while, and are very widely prescribed. However, these are extremely pernicious since they sometimes cause personalty change, obsessive shopping, gambling etc.
In 2004 I devised a reasonable etiological hypothesis for RLS/PLMD. In 2011 I refined this and sent it to the world's leading RLS/PLMD researchers. None replied. It is a perfectly good hypothesis which explains many observations. The briefest summary is that there is a uniquely human soft-touch activated foot withdrawal reflex response triggered by soft touch (in addition to the normal, painful, puncturing pin-prick sensation) on the foot arch. Only humans have foot arches and the skin there needs to be soft and flexible - and so is subject to puncture and debilitating infection.
I propose that this novel soft-touch activated foot withdrawal reflex response led to a separate novel circuit - inhibition in the lower spinal cord by dopamine, which is released by some descending neurons which are somehow non-consciously activated when there is a reason to inhibit this reflex response, such as (perhaps) walking on a surface which is in fact safe for the foot arches, since it has no spines or sharp edges. RLS/PLMD typically involves this descending dopaminergic inhibitory pathway not working properly. As far as I know, there are no problems driving the neurons. The problems are due to the neurons being unable to release sufficient dopamine to inhibit the sensitive soft-touch triggered reflex response, which can then be triggered by random noise in the soft-touch sensors in the foot arch. (These can be reduced or eliminated with local anesthetic on that skin, reducing or abolishing RLS/PLMD symptoms.)
Multiple processes drive RLS/PLMD by some combination of lower levels of activation of both dopamine and opioid receptors in the particular circuits which drive this withdrawal response. Similar circuits exist for the hands (palms) and torso, but these are not as strong as those for the foot arch.
One cause of reduced dopaminergic inhibition is the output terminals in the lower spinal cord running out of tyrosine, since they are converting into dopamine most of the time, including when we are sleeping or trying to get to sleep. A common cause of this is reduced physical activity, which reduces bloodflow into the spinal cord and, in particular, reduced circulation of cerebrospinal fluid there, causing a localised depletion of tyrosine. Percussive (not smooth) massage of the lower spine can fix this in seconds, abolishing or reducing symptoms for an hour or so.
So much for trying to summarise this! Please read the real summary, which includes further observations, and suggestions for avoiding the problem - including its lower level, insomnia causing, form - at: https://aminotheory.com/rlsd/briefsumm/ . Spinal injury is a leading cause of severe RLS/PLMD. Yet most researchers think the etiology is in the brain or brain stem.
Inadequate 25-hydroxyvitamin D surely increases the risk of RLS/PLMD too, but I don't know any specific mechanisms.
Thanks so much for the in-depth comment Robin! I included a bit of it into the post from today. That's really interesting about the whole role of stimulants. We tend to forget that caffeine is technically designated a drug. It properties go very deep and yet it's something many drink routinely without giving it much thought (including me).
That's a really interesting hypothesis Robin. I'm not sure why no one would at least respond. Do you know if much has happened in the field? I generally feel that science has a bit of a gatekeeping issue in which they don't like outsiders into their territory, and unless the ideas are brought forth from some expert in the field they may not decide to give it much thought.
I haven't kept up with RLS/PLMD research in recent years, but as far as I know, most researchers assume the etiology is in the brain - though they admit they don't know what it is. ("More research funding desperately needed!")
There are no non-human animal models of RLS/PLMD. The researchers keep thinking about the brain and brainstem, despite numerous lines of evidence showing the underlying cause of RLS/PLMD is a dysregulated, self-triggering, spinal reflex circuit which protects the foot arch. Perhaps the spinal cord is not so glamorous as doing _brain_ research. Also, there is generally thought to be no significant dopaminergic activity in the spinal cord - but this is based on research into non-human mammals. Everyone knows about dopamine regarding Parkinson's disease in the substantia nigra, so like people who keep looking for lost car keys under streetlights, rather than anywhere else, most researchers keep researching the brain, mid-brain and brain stem - despite there being no evidence that PD and RLS/PLMD are linked.
I regard the most important research on RLS/PLMD, at least until the last few years, as Bara-Jimenez et al 2000: https://sci-hub.tw/10.1212/WNL.54.8.1609 who showed that RLSD/PLMD muscle movements closely resembled a foot withdrawal spinal reflex response and that such a response could be triggered by a very small, non-painful, electric shock to the foot arch. This was largely ignored by all the other researchers in the 2000s. I think that the Bara-Jimenez people went off and researched other things - not RLS/PLMD.
One can reasonably conclude from this that medical doctors, PhD researchers and professors don't like being told by an electronic technician in Australia that there is room for improvement in their RLSD/PLMD research. Ideally, perhaps, I would have pursued this assiduously since 2011. However I put so much time into reading the literature from 2004, a 1000+ page neuroscience textbook and writing up my observations and hypotheses that I had to put it aside and concentrate on paying work. I was planning to create an annotated bibliography of the much neglected nutrient boron https://aminotheory.com/cv19/#08-boron in late 2019, but COVID-19 caused me to focus on vitamin D.
Thank you so much for this information on RLS - I have a friend who’s nearly at his wits end dealing with RLS - what the doctors have prescribed so far has done nothing to help.
Fascinating information about cytokines! I am looking forward to this series about improving health. This is literally useful and sadly doesn’t get the attention it deserves - seems we are too busy arguing about whether or not viruses exist. Well, take care of yourself (terrain theory) and you won’t get as sick when the germs come calling.
The cytokines are really interesting. Inflammation is implicated in so many things, and so it makes one wonder how deep the inflammation/sleep relationship goes. There was one study I looked at that examined fatigue and chronic inflammation and sleepiness. It would make sense. I suppose it's the body's way to try and "recover", but unfortunately sleep may not help it out much.
The viruses stuff is interesting. I'm not quite sure what's going on, but I hope we can have differing opinions without trying to take over people's own voices.
I am all onboard with the "need for sleep". Slept for 10 hours this Saturday and could not be happier.
But in many ways, good sleep, important as it is, is kind of like "good love life". Is it important to have "good love life"? You bet! But it is not easy to have "good love life" even if one decides to have it -- it is hard to get.
Sleep is also like this, so many commitments, BS etc. I have to wake up at 5:45am during the week days. Even though I love my job, I hate waking up at 5:45. Even though I own my business I cannot change this. Now as for going to bed early, I often start writing something in the evening, or read stuff like your substack etc. Cannot go to bed at 9pm.
Not so easy to have good sleep, even though it is 100% extremely important!!
Anyway, knowing what you wrote, I will try harder!
It's definitely true that modern life and work has made it difficult for many to get good night's rest. The main problem is that the body doesn't quite give a crap how much work we have. Our body just wants to tell us, "hey, get sleep now or you'll regret it later!" As much as we would like to tell it to not react so negatively.
It should kind of remind us that modernity can't get away from our biological processes that have been cultivated over hundreds of thousands of years.
Sleep is so important! Thanks for the reminder.
I hope you don't need a daily reminder to sleep. I think that's why they invented alarm clocks, or pets.
😄 I don't need a reminder. I get 8 hours every night unless I'm keeping myself up too late, which happens every once in awhile. This is what the good reminder is about, that I get into bed by 10:00 every night! Do you get good sleep regularly?
Great caption on sleep. And what interferes with it? Some of our cherished habits, like caffeine, and looking at this little screen in my hand or on my desk within a couple hours before going to bed.
Sleep is one of the low hanging fruits we can do for improving our health. I mean, I can exercise, I can take all the pills for anti-inflammatory, immune support, etc, but if I don't get my sleep, they aren't doing me that much good.
It's so easy to improve sleep, yet for as much outcry as we have over everything else going on so many people just don't seem to alert others to the need to get good sleep. It's probably one of the best things you can do for your own health!
Thanks for the link to the article "Sleep and inflammation: partners in sickness and in health" Michael R. Irwin, Nature Immunology 2019-07-09 https://www.nature.com/articles/s41577-019-0190-z (Paywalled, but available via Sci-Hub: https://sci-hub.se/10.1038/s41577-019-0190-z .) This is surely related to lack of darkness at night being associated with obesity and type 2 diabetes, since these are in part inflammatory disorders: https://www.trialsitenews.com/a/northwestern-study-links-light-during-sleep-to-obesity-diabetes-high-blood-pressure-in-older-adults-6ccb770a .
Alcohol is a sleep disruptor. So are many SSRI "antidepressants".
Caffeine is a terrible sleep disruptor, not just through its immediate effects a few hours after consuming it. Caffeine drives Restless Legs Syndrome / Periodic Limb Movement Disorder (RLS / PLMD, which are separate diagnostic criteria - sensation and movement - for the one underlying disorder). I didn't know this when I wrote a Letter about this https://www.liebertpub.com/doi/abs/10.1089/jcr.2014.0024 . I should make an updated version of this publicly available. There is an article from about 15 years ago I can't find right now which reports on people with RLS/PLMD whose problems went away after they stopped using caffeine.
It is my impression that caffeine withdrawal drives RLS/PLMD - the effects of consuming caffeine more than 3 hours or so beforehand. A small amount of caffeine may quell these withdrawal effects and so reduce RLS/PLMD for a while.
Chocolate contains caffeine, theobromine (which very similar to caffeine, and from which coffee plants make their caffeine) and other substances. Unfortunately there is something in chocolate which drives RLS/PLMD immediately and in the ~~3 to 6 hours which follow.
Coffee, but not tea or chocolate, contains opioid receptor antagonists. These surely directly disrupt sleep by reducing the level of background opioid receptor activation caused by endogenous opioids. See the research cited at: https://aminotheory.com/coffee/ . Opioid receptor antagonists also directly drive RLS/PLMD.
RLS/PLMD is a severe sleep disruptor - but I believe that the same processes, at a level which would not meet RLS/PLMD diagnostic criteria, are a powerful sleep disruptor too. I am sure this is very common, and that it is classified as idiopathic (no known cause) insomnia. I speak from personal experience. Actual RLS is noticeable disturbed sensations. Actual PLMD is toes and foot lifting up, and perhaps whole leg withdrawal reflex responses. Below this level, there can be a subtle but significant level of disturbance - it is difficult to get "comfortable" - which disrupts sleep.
The etiology of RLS/PLMD is officially unknown, though it is well known that shortage of iron drives it. This is easily understood in terms of iron being a co-factor for the tyrosine hydroxylase enzyme. This converts the common amino acid tyrosine into L-DOPA, which is then converted by another enzyme (which can usually be relied upon to work well) into dopamine. This occurs in the output terminals (axons) of neurons with the dopamine being stored in vacuoles, from which it is released into the synaptic cleft as a (typically inhibitory) neurotransmitter when the neuron fires.
Dopamine receptor agonists (which activate the receptor) and opioid receptor agonists (AKA exogenous opioids and those produced endogenously in the body) are well known to quell RLS/PLMD. Opioid drugs are highly addictive and debilitating - but are used for RLS when nothing else works. Dopamine receptor agonist drugs work for a while, and are very widely prescribed. However, these are extremely pernicious since they sometimes cause personalty change, obsessive shopping, gambling etc.
In 2004 I devised a reasonable etiological hypothesis for RLS/PLMD. In 2011 I refined this and sent it to the world's leading RLS/PLMD researchers. None replied. It is a perfectly good hypothesis which explains many observations. The briefest summary is that there is a uniquely human soft-touch activated foot withdrawal reflex response triggered by soft touch (in addition to the normal, painful, puncturing pin-prick sensation) on the foot arch. Only humans have foot arches and the skin there needs to be soft and flexible - and so is subject to puncture and debilitating infection.
I propose that this novel soft-touch activated foot withdrawal reflex response led to a separate novel circuit - inhibition in the lower spinal cord by dopamine, which is released by some descending neurons which are somehow non-consciously activated when there is a reason to inhibit this reflex response, such as (perhaps) walking on a surface which is in fact safe for the foot arches, since it has no spines or sharp edges. RLS/PLMD typically involves this descending dopaminergic inhibitory pathway not working properly. As far as I know, there are no problems driving the neurons. The problems are due to the neurons being unable to release sufficient dopamine to inhibit the sensitive soft-touch triggered reflex response, which can then be triggered by random noise in the soft-touch sensors in the foot arch. (These can be reduced or eliminated with local anesthetic on that skin, reducing or abolishing RLS/PLMD symptoms.)
Multiple processes drive RLS/PLMD by some combination of lower levels of activation of both dopamine and opioid receptors in the particular circuits which drive this withdrawal response. Similar circuits exist for the hands (palms) and torso, but these are not as strong as those for the foot arch.
One cause of reduced dopaminergic inhibition is the output terminals in the lower spinal cord running out of tyrosine, since they are converting into dopamine most of the time, including when we are sleeping or trying to get to sleep. A common cause of this is reduced physical activity, which reduces bloodflow into the spinal cord and, in particular, reduced circulation of cerebrospinal fluid there, causing a localised depletion of tyrosine. Percussive (not smooth) massage of the lower spine can fix this in seconds, abolishing or reducing symptoms for an hour or so.
So much for trying to summarise this! Please read the real summary, which includes further observations, and suggestions for avoiding the problem - including its lower level, insomnia causing, form - at: https://aminotheory.com/rlsd/briefsumm/ . Spinal injury is a leading cause of severe RLS/PLMD. Yet most researchers think the etiology is in the brain or brain stem.
Inadequate 25-hydroxyvitamin D surely increases the risk of RLS/PLMD too, but I don't know any specific mechanisms.
Thanks so much for the in-depth comment Robin! I included a bit of it into the post from today. That's really interesting about the whole role of stimulants. We tend to forget that caffeine is technically designated a drug. It properties go very deep and yet it's something many drink routinely without giving it much thought (including me).
That's a really interesting hypothesis Robin. I'm not sure why no one would at least respond. Do you know if much has happened in the field? I generally feel that science has a bit of a gatekeeping issue in which they don't like outsiders into their territory, and unless the ideas are brought forth from some expert in the field they may not decide to give it much thought.
I haven't kept up with RLS/PLMD research in recent years, but as far as I know, most researchers assume the etiology is in the brain - though they admit they don't know what it is. ("More research funding desperately needed!")
There are no non-human animal models of RLS/PLMD. The researchers keep thinking about the brain and brainstem, despite numerous lines of evidence showing the underlying cause of RLS/PLMD is a dysregulated, self-triggering, spinal reflex circuit which protects the foot arch. Perhaps the spinal cord is not so glamorous as doing _brain_ research. Also, there is generally thought to be no significant dopaminergic activity in the spinal cord - but this is based on research into non-human mammals. Everyone knows about dopamine regarding Parkinson's disease in the substantia nigra, so like people who keep looking for lost car keys under streetlights, rather than anywhere else, most researchers keep researching the brain, mid-brain and brain stem - despite there being no evidence that PD and RLS/PLMD are linked.
I regard the most important research on RLS/PLMD, at least until the last few years, as Bara-Jimenez et al 2000: https://sci-hub.tw/10.1212/WNL.54.8.1609 who showed that RLSD/PLMD muscle movements closely resembled a foot withdrawal spinal reflex response and that such a response could be triggered by a very small, non-painful, electric shock to the foot arch. This was largely ignored by all the other researchers in the 2000s. I think that the Bara-Jimenez people went off and researched other things - not RLS/PLMD.
A new line of research does focus on the spinal cord: Dafkin et al. 2019: https://sci-hub.tw/10.1016/j.smrv.2019.05.005 . I wrote to them a year or so ago and got no reply.
One can reasonably conclude from this that medical doctors, PhD researchers and professors don't like being told by an electronic technician in Australia that there is room for improvement in their RLSD/PLMD research. Ideally, perhaps, I would have pursued this assiduously since 2011. However I put so much time into reading the literature from 2004, a 1000+ page neuroscience textbook and writing up my observations and hypotheses that I had to put it aside and concentrate on paying work. I was planning to create an annotated bibliography of the much neglected nutrient boron https://aminotheory.com/cv19/#08-boron in late 2019, but COVID-19 caused me to focus on vitamin D.
Thank you so much for this information on RLS - I have a friend who’s nearly at his wits end dealing with RLS - what the doctors have prescribed so far has done nothing to help.
Fascinating information about cytokines! I am looking forward to this series about improving health. This is literally useful and sadly doesn’t get the attention it deserves - seems we are too busy arguing about whether or not viruses exist. Well, take care of yourself (terrain theory) and you won’t get as sick when the germs come calling.
The cytokines are really interesting. Inflammation is implicated in so many things, and so it makes one wonder how deep the inflammation/sleep relationship goes. There was one study I looked at that examined fatigue and chronic inflammation and sleepiness. It would make sense. I suppose it's the body's way to try and "recover", but unfortunately sleep may not help it out much.
The viruses stuff is interesting. I'm not quite sure what's going on, but I hope we can have differing opinions without trying to take over people's own voices.