Insomnia may be common but much is still unknown about it. We know, for instance, that different types of insomnia exist, but the authors of a recent paper “Effects of trazodone versus cognitive behavioral therapy in insomnia with short sleep duration phenotype: a preliminary study” report that attempts to define them based on whether they are primary or secondary, age of onset, or even objective sleep findings have, for the most part, failed. The answer, they believe is to go beyond the ordinary sleep findings and look deeper at what’s going on in the body.
Interestingly, they’ve turned to a subject of interest in chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) – the stress response system in order to better understand insomnia.
Check out the 4th part of an ongoing sleep series:
- Sleep Pt. I: Why We Sleep (and What Happens When We Don’t)
- Why We Sleep Pt II: Walker on the Dark Side of Sleeping Pills and a CBT That Works?
- The Sleep Issues in Fibromyalgia: an Overview
Two Types of Insomnia
ISS – the Stress Response Insomnia – Not many studies have been done but the authors believe the results have allowed them to identify two distinct types of chronic insomnia: one called ISS (insomnia with short sleep and stress activation) produces insomnia and shortened sleep is associated with “physiological hyperarousal“; i.e. activation of the stress system and potentially a host of negative side-effects (hypertension, diabetes, cardiovascular disease, increased mortality.
INS – The Anxious Insomnia – Insomnia with normal sleep duration (INS) is not associated with increased mortality, etc. but is associated with anxiousness and a tendency to ruminate. Note people with INS have normal sleep duration – they just have trouble falling asleep. That probably does not fit most people with ME/CFS/FM.
Treatments
ISS (Stress Response Insomnia) Treatment – ISS (the stress response sleep disorder) is treated with drugs aimed at decreasing the hyperarousal, in particular, the HPA axis activation the authors believe is occurring during sleep. The two drugs they’ve focused on – doxepin elixir and trazodone – have long been used in ME/CFS/FM. Doxepin elixir was a favorite of Dr. Cheney – who years ago lauded its histamine-reducing properties. (Trazodone is a weaker histamine blocker.)
Trazodone, the second-most prescribed drug for insomnia, is also known to downregulate HPA activity. Trazodone has long been a go-to drug for sleep among ME/CFS/FM doctors. Other sleep drugs such as benzodiazepines and benzodiazepine receptor agonists do not downregulate the HPA axis.
INS- Anxious Insomnia – INS is usually treated with cognitive behavioral therapy for insomnia (CBT-I). According to the authors, CBT-I – a management tool – can produce insomnia remission rates of 50%–60% and significant symptom reductions in 75%–80% of patients. Interestingly, it does not appear to be particularly good at improving sleep duration in people who get too little sleep. It’s more able to help people get to sleep and reduce symptoms.
Whether or not people with ME/CFS/FM have hyperarousal sleep patterns or not, CBT-I might be something worth trying given the anxiety and changes to sleep times and rhythms that accompany poor sleep in these diseases.
Given that ISS is associated with an activated stress response system and CBT-I attempts to reduce anxiety it perhaps stands to reason that it might help with ISS. These authors believe, though, that more aggressive treatment is needed to get at the pathologically activated stress systems in people with ISS. Studies have found that CBT-1 is more effective in people with insomnia and normal sleep duration than in people with insomnia and shortened sleep.
The Study
The authors tested their hypothesis that HPA axis inhibiting drugs work better in insomniacs with ISS than in insomniacs with INS in a quite small, preliminary study (n=15) study which was randomized but also open-label (everyone knew what treatment they were getting) The treatments (drugs vs CBT-I) were randomized and actigraphy (done for several 2-week periods), salivary cortisol (five time-points during three periods), and the insomnia severity index assessments were done.
The CBT-I treatment included de-catastrophizing, constructive worry, and cognitive restructuring techniques. Trazodone (25-100 mg) was taken for 9 months.
Results
Trazodone “significantly and markedly” lengthened objective sleep duration by about 50 minutes both at the post-treatment time point and at long-term follow-up. It also reduced cortisol levels by a whopping 36% “in a clinically meaningful manner”. That the cortisol reduction was only “marginally significantly associated” with the increased sleep duration pointed to the possibility that upregulated cortisol during sleep was reducing sleep times but did not nail it.
The authors noted, though, that the HPA axis reduction/increased sleep time made sense as studies have shown that activating the HPA axis by intravenously injecting corticotrophin-releasing hormone produces increased wake times and reduced sleep times.
One fly in the ointment did possibly show up during the long-term assessment. A reduced drop in cortisol levels (from 36%-21%) suggested that long-term use of trazodone might result in tolerance. The study was so small, though, that other variables may have come into play, and ME/CFS doctors suggest the drug maintains its effectiveness long term.
ME/CFS and Fibromyalgia – Does the hyperarousal HPA axis sleep pattern apply?
HPA Axis
With regard to the HPA axis, salivary morning cortisol levels tend to be reduced (not increased) in ME/CFS. Cortisol in fibromyalgia, on the other hand, appears to be increased including at nighttime. Unfortunately, sodium oxybate (Xyrem) did not get FDA approval for FM, but this alpha-wave reducing drug also apparently reduces morning cortisol levels. A couple of studies, though, have found low cortisol levels in FM.
The Gist
- The authors propose that two different kinds of insomnia exist. One – called ISS – is driven by a pathological hyperarousal of the HPA axis which results in shortened sleep times and increases the risk of several serious conditions. The other – called IND – is a more anxiety-driven type of insomnia that does not result in shorter sleep times overall or negatively affect health overall.
- The first – which fits ME/CFS/FM better – is best treated, they believe, by drugs that tamp down the stress response. The second type of insomnia is best treated by cognitive behavioral therapy for insomnia (CBT-I).
- The reduced parasympathetic nervous system activity found during slow wave (deep) sleep in ME/CFS and increased cortisol levels in fibromyalgia suggest that hyperarousals could be affecting sleep in these diseases. (Note, though, that low morning salivary cortisol is found in ME/CFS.)
- Two sleep medications (low-dose trazodone, and Doxepin elixir) were proposed to reduce central nervous system hyperarousal and improve sleep. The small study assessed trazodone’s effectiveness in doing so and found that it substantially reduced cortisol levels, significantly improved sleep times by 50 minutes, and improved sleep overall. It was more effective in almost all ways than CBT-I.
- Trazodone has been recommended by ME/CFS experts before and may be the least likely drug to lose effectiveness over time. It may also be able to reduce neuroinflammation. Doxepin elixir, on the other hand, appears to have better histamine-reducing properties.
- Some time ago, a drug repurposing company proposed that trazodone + low dose naltrexone might prove particularly helpful in ME/CFS.
Autonomic Nervous System
A 2012 review noted that sleep study results in ME/CFS tend to be all over the map. For instance, some people with ME/CFS sleep too little while others sleep too much. Some studies have found evidence of alpha-delta intrusions that interrupt sleep while others have not. The amount of slow-wave, or deep, sleep may or may not be reduced. (One study found it was increased.) The heterogeneous nature of these diseases, the heterogeneous diagnoses used in study criteria, the inadequate state of testing, or other factors may contribute.
Interestingly, one finding that has seemed to hold up is a state of autonomic nervous system hypervigilance (reduced parasympathetic nervous system activity). One study found that low heart rate variability (HRV) was the best predictor of subjective sleep quality. Personally, my Oura ring and Garmin watch at times show remarkably high sympathetic nervous system activity (i.e. stress) levels during sleep.
Several studies suggest that the other stress response system – the autonomic nervous system – may be aroused during sleep as well. Several have found reduced parasympathetic nervous system activity during the deep stages of sleep (and NREM2) in ME/CFS, which is associated with reduced self-reported well-being and sleep quality. The authors of the most recent study in 2020 suggested that the reductions in parasympathetic nervous system activity may be inhibiting “the energy recuperation” that normally occurs during slow-wave sleep.
They proposed that even people getting normal amounts of slow-wave sleep may not be getting the benefits their sleep apps might suggest they are getting. They suggested that treatments designed to inhibit sympathetic nervous system activity and plump up parasympathetic nervous activity during deep sleep could be helpful.
Trazodone
Trazodone is a triazolopyridine derivative that is structurally more closely related to other triazolopyridine-derived drugs than the drugs that make up major classes of antidepressants.
By inhibiting the reuptake of serotonin and blocking the histamine and alpha-1-adrenergic receptors, trazodone reduces levels of neurotransmitters (serotonin, noradrenaline, dopamine, acetylcholine, and histamine) that are associated with arousal.
Trazodone is also classified as a “weak histamine antagonist”, but its histamine-blocking effects could conceivably be helpful in people with mast cell activation syndrome (MCAS). It may also inhibit neuroinflammation.
Some limited evidence suggests that trazodone may be able to regulate autonomic nervous system functioning as well. Trazodone reportedly helped with a disease called Barré-Lièou Syndrome (BLS), which sounds like a close cousin to ME/CFS and FM. BLS is characterized by autonomic and other symptoms including muscle stiffness, tinnitus, dizziness, insomnia, and widespread pain. It’s believed to be caused by hyperactivation of the autonomic nervous system due to trauma. Trazodone was found to “safely and effectively” treat it.
Mathew Walker has inveighed against the use of sleep drugs because he reports that they don’t improve sleep architecture and are associated with detrimental long-term effects. A recent review of trazodone (and other antidepressants as well as anticonvulsants and antipsychotics) reported that it and the other drugs had “a beneficial effect on sleep architecture” but may suppress REM sleep.
An interesting 2008 study suggested that trazodone may enhance the benefits of mindfulness practices such as cognitive-behavioral therapy (CBT) in some people. A small 2008 study found CBT plus trazodone resulted in greater increases in deep, slow-wave sleep in people with depression.
Trazodone For Chronic Fatigue Syndrome and Fibromyalgia
The IACFS/ME Primer for Clinical Practitioners states trazodone may be the sleep drug “least likely to lose effectiveness over time”.
A 2011 open-label FM study found that trazodone had the greatest effect on sleep, markedly improved sleep quality, sleep duration, and sleep efficiency, and also had moderate effects on other symptoms such as anxiety and depression scores and pain interference with daily activities. The authors called the improvement of sleep quality ‘striking’.
Another 2011 open-label FM study by the same group found that trazodone helped with “global fibromyalgia severity, sleep quality, and depression, as well as pain interference with daily activities”. When Lyrica (pregabalin) was added, there were further improvement improvements in morning stiffness, pain (body pain and pain severity), and anxiety. An interesting placebo-controlled 2018 study found that in Vit. D deficient fibromyalgia patients, trazodone (25 mg) given at bedtime + vitamin D 50 000 IU (international units) weekly significantly improved pain and sleep scores.
A Spanish FM study suggested that low doses can effectively enhance sleep but that higher doses are needed to affect depression and FM symptoms.
Dr. Lapp reports that he has “excellent luck” with Trazodone, and Dr. Bell states that “Trazodone is one of my most favorite medications for sleep. Trazodone doesn’t cause dry mouth or stimulate the appetite (no weight gain) and puts you into deep stage three or four sleep.”
Since it works best in the early morning hours it is a good medication for those who wake early and can’t get back to sleep. It also helps with anxiety. Men may find that it may help with erections.
Trazodone + Low Dose Naltrexone for ME/CFS?
Trazodone has been recommended by several ME/CFS experts, but the most interesting part of the trazodone saga in ME/CFS concerns the hunt for a repurposed drug for ME/CFS that occurred about a decade ago. The CFIDS Association of America (now Solve M.E.) funded a firm called Biovista to analyze mounds of data and come up with an already approved drug/drug combo that could help people with ME/CFS.
Biovista identified a two-drug combo: trazodone plus low-dose naltrexone (LDN) – that it proposed could tamp down neuroinflammation. The findings were interesting because neither the trazodone nor the low-dose naltrexone drug trials had been published – yet Biovista pegged this drug combination as promising.
Dose – Trazodone should be taken at least an hour before bedtime to treat sleep-onset insomnia. Dr. Bell starts at 25 mg (taken ½-2 hours before sleep) and works his way up (50-150 mg). Dr. Lapp recommends 50 mg.
Side Effects – Tachycardia is not normally associated with trazodone, but it was experienced by 32% of patients in a fibromyalgia study and was the most common reason for discontinuing trazodone in a Spanish FM study. That led the authors to suggest that autonomic nervous system abnormalities in FM may leave some patients more susceptible to tachycardia. Other possible side effects that might be particularly pertinent for ME/CFS/FM patients include low blood pressure, dizziness, light-headedness, and fatigue.
Conclusions
The authors of this interesting study propose that two different kinds of insomnia exist. One is driven by a pathological hyperarousal of the HPA axis which results in shortened sleep times and increases the risk of several serious conditions. The other is a more anxiety-driven type of insomnia that does not result in shorter sleep times overall or negatively affect health overall. The first – which fits ME/CFS/FM better – is best treated, they believe, by drugs that tamp down the stress response. The second is best treated by cognitive behavioral therapy for insomnia (CBT-I).
Given the evidence of reduced parasympathetic nervous system activity during slow wave (deep) sleep in ME/CFS, and the findings of increased cortisol levels in fibromyalgia, the idea that hyperarousals are affecting sleep in these diseases makes sense. On the other hand, the low morning salivary cortisol levels found in ME/CFS, suggest the opposite might be happening with in the HPA axis. Clearly, more study using more fine-tuned assessments is needed concerning sleep in these diseases.
The two sleep medications (low-dose trazodone, and Doxepin elixir) proposed by the authors of this study to reduce central nervous system hyperarousal are, interestingly, in fairly common use in ME/CFS/FM and appear to be commonly used overall. Trazodone was found to reduce cortisol levels by about a third and was associated with substantially long sleep and better sleep overall. Trazodone may also be able to reduce neuroinflammation. Doxepin elixir, on the other hand, appears to have better histamine-reducing properties.
I just wanted to note that Xyrem, while it has definitely helped some people, made me deathly ill and destroyed my stomach for years. (Lost 35 lbs in 3 weeks). It is an orphan drug with only about 365 people in the clinical trial and Jazz Pharmaceutical refused to test it against a lot of common drugs (like antibiotics) for interactions. In fact, there are many drugs it interacts with. Also, It is a derivative of GHB, the date rape drug, and causes disorientation, paralysis, hallucinations, memory loss, etc. Sure, it helped me get more Stage 3 sleep but it also made me think my closet was a bathroom. Sleep walking, sleep eating, sleep driving. Again, it has really helped some people but it is a very scary drug. People should just be aware that there are good reasons this drug is not widely available.
I have had some success with Ativan. My new GP switched me to Temazepam but it gives me terrible nightmares and less restful sleep. I will ask about trazadone. I have had 3 sleep studies and 1 daytime sleep study done over the years. Nothing normal about my sleep at all. Good to see they are starting to differentiate between different Ty of sleep issues.
Hello Sally K. after reading your post I just wanted to advise not going down the road of benzodiazepines ie Ativan, temazepam. They have an awful history if you look up Benzo withdrawal. When they quit working for me I tried to stop taking them and it was a nightmare. I had to slowly taper over 3 years. I have since been taking trazodone 25 mg for about 12years. It worked very well for most of this time. I am wondering if I am finally reaching a tolerance as it works good for about 4 hours then I need to take another small piece to get me through the night. Any way just my 2 cents! Best of luck to you.
I had exactly the same experience on Xyrem! The weight loss was great for me but the sleep walking and severe anxiety in the morning were not worth it. I still only slept about 4- 5 hours. Probably a deeper sleep though. Xyrem is not for me!
trazodone never helped for ME/cfs and over decades the side effects got worse and worse.
ihope there will be finally be more good gig research on all the sleepproblems that excists i me/cfs and other illnesses. cbt is a joke, sorry, been there, done that…
Diagnosed with CFIDS/ME 29 years ago, I went through all the less toxic sleep remedies and after that ended up on Ambien. It has worked for me for at leaast 20 years! Either that or my sleep issue has resolved by now and the Ambien is a placebo! No way to learn. Does anyone know of studies of pts. with CFIDS/ME who have been on Ambien long-term (really, really long-term?)
Congratulations on finding something that has worked with sleep and continues to do so. 🙂
Thank you so much for this article! I’m struggling to stay asleep . Go to sleep well, but once I wake up in middle of night, I cannot go back to sleep.
This insomnia makes everything so difficult. I have taken these drugs before, but will revisit. I so desire to have no frogs and sleep like everyone else seems to. This explains the problem!
I meant … no drugs! Not frogs!😁
Don’t our foggy brains come up with some doozies. But frogs sounded cool too. 😊
I have an Oura ring. It notes my heart rare dropping. Is there other signs of stress?
Significant increases in temperature and drops in heart rate variability and two other ones. Increased heart rate is a biggie. Some people’s heart rate may increase or decrease when they’re under stress.
I’m of like mind. I didn’t try Trazodone until my sleep worsened and I felt I had to try something. Luckily, it’s helping.
I may try doxepin and rotate the two if both work. I’m all for drugs now! (lol)
I think your on to something, Cort.
I took Trazodone for years and eventually gained enough tolerance that I could no longer increase the dose without adversely affecting Pots (via lowering morning blood pressure).
Now I rotate between Trazodone with low dose melatonin and doxepin with low dose clonazapam. Had I done this rotating from the start, I think my ME would have been much easier to manage.
Thanks, David – I’m worried about tolerance to high THC cannabis as well. Good to rotate if possible. 🙂
I don’t know if/where this fits in, but histamine (a constant problem, the source of most of my POTS symptoms) always gives me terrible insomnia, of the ‘why even bother going to bed’ kind. I follow a low histamine diet most of the time, but one averagely histamine-containing meal will destroy that night’s sleep. If I eat averagely histamine-containing foods every day then I’m a 24/7 brain fogged mess and sleep all the time.
I have the same issues. Have you had a 24 hour saliva cortisol done? I get mine from DiagnosTechs(.com) through my DR. My am cortisol is too low and night time is too high. Histamine supposedly peaks at 3am, right when I wake up when my histamine is too high. Since I’ve started a low histamine diet I now wake at more scattered times from 12:30 to 4:30a. If cortisol and histamine are connected then that makes sense. Now to find a way to get them both down. This report looks helpful. 🙂
Hi T Allen
I did, a very long time ago – it showed that my cortisol rose in the early morning as it should and then just flatlined for the rest of the day. I should test it again, I think.
Interesting! I was wondering if there was a way that low morning cortisol levels could reflect high night-time cortisol levels. Apparently so. Cheney was so enamoured of the histamine blocking properties of doxepin elixir.
If I remember correctly, he thought histamine was a master immune regulator – he was way ahead of his time.
I have found CBT is no match for the serious physical symptoms we have with ME/CFS. Has anyone found CBT to be helpful for sleep? Trazadone works for me. No side effects that I know of.
Glad to hear that trazodone is helping.
We’ll have more on CBT-I or CBT for insomnia in a later blog. In her course, Eleanor Stein recommends giving it a try. (There are books on it.) These authors don’t feel CBT-I is a match for hyperarousal sleep problems – but I imagine it could be helpful. Every little bit helps.
A 2021 meta-analysis of fibromyalgia studies found “CBT-i was associated with a significant improvement in sleep quality, pain, anxiety, and depression, although these results are retrieved from very few studies with only very low to low quality evidence. ”
https://pubmed.ncbi.nlm.nih.gov/34297651/
I agree every bit helps. I have found being a self-aware, mature person to be helpful. I’m dedicated to my quality of life and never create drama or chaos out of it, because I can’t afford that in my life.
If I broke my leg, I’m better off for being a mature, self-aware person, but I wouldn’t think CBT would be helpful for re-setting the bone or holding it secure while it mends, or stopping the initial acute pain. CBT would only be helpful on the very edges of such an episode and a doctor would never suggest it after an x-ray. She would set the bone, put a cast on, give me crutches and probably some painkillers. This might seem like a simplification, but I think not by much.
Hi Cort,
In the course of investigating your own sleep issues, did you communicate directly with Lapp, Cheney, or Bell? If so, did any of the 3 seem particularly MORE interested in the relationship between MECFS and Sleep? I tried reaching out to a few of my own connections in the research community, but their energies were being consumed in other areas and they weren’t really able to get into the sleep end of matters (which is unfortunate as sleep is extremely complicated and what can help one person can exacerbate problems in another). Likewise, it’s disappointing that I was pursuing these communications while some of the best minds in sleep medicine were still with us. Everyone I knew that was considered a “Great” in the world of real sleep medicine (a very different thing from the factory farm that cashes in on sleep apnea today), has passed away. I do have personal written and detailed reports written by one though that explain the phenomenon of insomnia/microarousals due to a depressed neurological state (not in the mental health way, but in the physiological sense of excessively low vital statistics, e.g. heart rate, respiration rate) and how this relates to triggering microarousals throughout the night and a failure to achieve stages 3 and 4 sleep. There are a ton of us who have depressed autonomic nervous systems, complete with POTS, NMH, who are being harmed by being prescribed sedatives, when in fact what we need are stimulants to help us achieve deep sleep, but it’s been very difficult finding any researcher in the world of MECFS interested in learning more about this. If any of the researchers seemed especially interested in the role of sleep and MECFS, I’d appreciate the name of the specific researcher. Unfortunately, my health has declined a lot since the days when I was more aggressively trying to pass the data along and arrange meetings between MECFS and Sleep Researchers. Now my hope is just that the data is gone for good after I pass away, creating a situation of the wheel having to be reinvented. Thanks in advance.
I got an odd reaction to Trazadone; at first it made me sleepy and then I suddenly would wake up at around 5:00 a.m. and could not fall back to sleep. Happened every time I took it.
I have some kind of hypersomnia where I can’t help falling asleep for several hours most days (around 6:00-8:00 p.m.). Like others with EDS I often get a burst of energy (tired/wired) around 10:00 p.m. and don’t feel ready to go to bed until midnight. EDS experts theorize that this has something to do with a very touchy, easily activated autonomic nervous system which can switch on even during sleep!
I’m ‘sleeping’ for at least 7 hours every night but with so many hot flashes/night sweats and restlessness because of pain, it’s probably very poor quality. Tried everything for them but they are still severe and frequent.
Clearly there is some kind of circadian rhythm issue going on too and I find it impossible to fight what my body wants to do.
When I do ‘ruminate,’ which is rare, a cannabis gummy takes care of it most effectively!
Trazodone – which I just started – and high THC cannabis are the only two sleep aids that have worked for me. My sleep has been getting worse lately. My brother found that melatonin plus trazodone helped him and so I tried it (50 mg). In general I found I sleep more and definitely feel more rested. Hopefully, that will continue!
I tried Trazadone, but makes my heart pound..🥴
A fibromyalgia study found some patients experienced tachycardia. How about doxepin elixir – the other sleep drug mentioned by this group?
Hot flashes / sweating spells during sleep = hypoglycemia
Have you tracked your blood glucose through out the day?
If that gumny is made with sugar and gelatin, it might be helping you in more than one way…
When you say sleepy around 6:00 to 8:00 pm – does it correspond with sunset? I am very sensitive to light/darkness and get sleepy at sunset. Of course the time varies through out the seasons.
I’m learning not to push through it, as that leads to the second wind and more stress hormones
Hi Cort,
What Trazadone dose are you on? Are you worried about the priapism side effect?
50 mg before bed and 25 mg if I wake up in the middle of the night. I’m also taking it with melatonin – and sometimes I’m mixing in some high THC cannabis. I have the idea that a little priapism might be nice but all joking aside haven’t experienced that.
My experience with my garmin watch is also that my parasympathetic vs sympathetic ‘stress’ score is high when I’m asleep, most nights and usually in all sleep stages. And the stress scores plot across the night corresponds to sleep quality (or lack of it). I’m mecfs 25 yrs, housebound.
There’s a great facebook group called Beat Long Covid With A Smartwatch which is mostly about using smartwatch stats for pacing and avoiding pem. They are happy to have mecfs people join. Almost everyone on there reports the same thing: too much sympathetic and not enough parasympathetic when asleep. (For garmin users, that’s horror nights if orange stress scores vs better quality sleep on nights with more blue. )
Very interesting that our sleep is not good quality. My daily resting heart rate can be and often is, higher than my sleeping heart rate. Will stash this away for when I eventually find a gp who can help.
Cort, a while ago – over a year I think, you mentioned a gadget that was proving helpful. I read your stuff on the Ouza ring so I wondered if it was something new? You mentioned your Oura above – is it still helpful? I use my apple wach to monitor heart rate but I’m not impressed with its HRV reading. I used polar 10 for a while but it was too temperamental to fix if the connection dropped. How about the oura?
Whoops – I meant daily rhr LOWER than sleeping HR. Soz!
It was the Garmin watch – which provides a body battery and a stress gauge throughout the day. I thought I would be using it more to determine when to rest and when to work and to track how effective meditation is – but I just haven’t done it.
I like the Garmin (it is expensive) but I still focus more on the Oura. I really like the Oura’s tips, its user-friendly layout, it’s Rest Day warnings, and it’s measurement of HRV. I don’t know how accurate the HRV is but mine plummeted a couple of months ago and has stayed low. Not sure why that is – I was doing a couple of things and something went haywire.
I would think your nightly resting heart rate would be much lower than daily! Sure sounds like hyperarousal. I was taken by the fact that the Australian sleep study looked at all sorts of parameters but found that only low HRV was associated with poor sleep.
It feels like my sleep disorder involves hyperarousal, but not manifesting as a short sleep duration, but manifesting as not being able to calm down the nervous system and get tired in the evening, resulting in late going-to-sleep times.
Only at times when circumstances result in having to push over consecutive days, resulting in a continous state of high arousals, it manifests also in shorter sleep duration.
I think hyperarousal of nervous system is definitely involved in my ME/CFS condition.
What I use for calming arousal before bedtime is 0,5-1mg melatonine and/or low dose trimipramine. I use trimipramine as a on-demand medicaton. Trimipramine calms the central nervous system I think. I also use it in the beginning of crashes to be able to rest better. Trimipramine is I think a tricyclic antidepressant, according to a sleep ambulance I’ve been to there is an established off-lable use of different tricyclic antidepressants for helping to go to sleep, with the added benefit that these are non-addictive sleeping aids. (Only thing I am not sure about is that a listed side effect of trimipramine is sensory hypersensitivity, so I am not sure if in theory – it could contribute a bit to my ME/CFS sensory hypersensitivities. But when I take it it rather seems to shield me a bit.)
Another doctor said melatonine also reduces cortisol levels (which sounds to me like down-regulating stress?).
About 2 weeks ago I started taking pregnenolone (a hormone precursor) – 10 mg in the morning and 10 mg before bed- and it seemed to also calm me down in the evening.
Pregnenolone is mostly made by the adrenal glands in the body, and then converted to DHEA and many other hormones in the body, like testosterone resulting from DHEA conversion, and cortisol from pregnenolone. (A picture of conversion chains can be found here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857441/ ).
The reason I am taking pregnenolone and also plan to try DHEA is that I have almost no DHEA and other male hormones like testosterone. According to some “adrenal exhaustion” hypotheses, his could be a consequence of continuous stress i.e. hyperarousal which over time “exhausts adrenal glands”. (Like poor glands just can’t keep up with continuos over-demand). But I’ve also seen mentioned low testosterone/DHEA in connection with latent EBV, though I dont know the scientific source.
Though some people take hydrocortisone to help with “adrenal exhaustion”, a book on “adrenal exhaustion” by J. L. Wilson warned against this as taking cortisone as the end product of hormone production chains in the body will result in a feedback loop in the body that dampens the body’s own cortisol production, and will therefore – if discontinued too suddenly like all cortisone medications – result in a cortisol deprivation state, or – if I remember correctly – might even involve a risk of the signaling system breaking down? The idea is that taking hormone precursors like DHEA or pregnenolone for a limited time messes less with signaling feedback loops in the body, as the body can take from the precursors what it needs to then produce many different hormones from it. There is also a chapter on “adrenal exhaustion” in the popular thyroid book by Datis Kharrazian.
DHEA is also involved in energy metabolism as far as I know.
I plan to try DHEA and pregnenolone to try and “relieve my adrenal glands” for some time and thereby “fill up” hormone levels in the body that are possibly depleted as a result of continous arousal. (Unfortunately I have no pre-illness hormone levels to compare to to say for sure).
DHEA and pregnenolone already helped me once in the begnning of my illness when it was mild. I then discontinued them by the time I started to develop pimples on my back and chest, which I took as a sign that male hormones were filled-up enough and more would cause akne-type spots).
I don’t expect hormone precursors to be curative for ME/CFS as a whole, but maybe rather help with one of many areas of disregulation involved and help relieve one layer of fatigue.
Couple of weeks ago I first tried DHEA (though recommendation is to take it in the morning, but i instead took some right before sleep which seemed to improve energy in the morning). Now I started on pregnenolone.
I will try to report on the effects,
Correction: “I’ve also seen mentioned low testosterone/DHEA in connection with latent EBV” is probably incorrect – misremembered this interesting finding on EBV blocking VitD3 receptors: https://pubmed.ncbi.nlm.nih.gov/20593215/
And another correction on hydrocortisone (it seems one should not quote books from memory…):
In more severe cases of low cortisol Dr. Wilson’s book does regard temporary supplementation of natural hydrocortisone as one treatment option, which can also be combined with animal adrenal extracts. There are other treatment options, too.
I have taken a combination of Trazadone and Temazpam for several years. They are the only thing that helps me get a good nights rest. I’d love to use CBD but being on an opioid that’s a big no-no, I’d flunk my urine screens for sure!
The “usual” sleep disorder recommendations, e.g. avoiding blue light in the evening (recommend apps like F-lux), no caffeine after midday, dose of bright natural sunlight in the late morning to reset body clock also help. If energy permits, oing for a walk in the evening to relieve tension and/or letting the body experience sunset can also help me.
None of this makes any sense to me personally. All antidepressants and antihistamines induce restless legs syndrome -Willis Ekbom Disease- in me, and make me sick as a dog. RLS a really serious condition and frequently co-morbid with fibromyalgia, EDS and all that sort of thing. It’s to do with glutamate hyperarousal, dopamine dysfunction, low iron… a whole different story. All those fibro drugs they tried to impose on me over the years just made me worse and the insomnia more debilitating. I can’t believe doctors who promote these one drug regimes and think it’s all so fantastic and make it seem like the one and only solution for all. I also have never had any issues with ordinary hypnotics, not in 20 years. But doctors just refuse to believe they can be helpful to some. And so they just keep pushing their uninformed agenda on me telling me I must be making it all up. And yet benzos are known to lower serotonin over activity in many conditions, not least serotonin syndrome.
Hello Evily.
Magnesium is the most plentiful electrolyte in the body, and is the first go-to for RLS, How have you fared wit taking it in a 1:2 ratio with calcium near bed time?
That is, twice as much calcium as magnesium?
Like Vit D, 50 % of people are magnesium deficient, which results from poor farming practices leading to depleted sool, resulting in low magnesium in our agri-food plants
Thanks but I had it checked and I have no deficiency. I think it would be impossible on the plant based diet I follow. Magnesium has not been validated by science as a cure for WED/ Restkess legs syndrome. It’s considered an old wife’s tale unless you do of course have a deficiency. Lastly, it aggravates the WED/RLS for me.
Vivi-Mari:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9804944/
I do not have a problem with old wives.
The fact that they may consistently recommend something moves me to try it,
or at least test the science, but not reject it outright.
the article above is science and does confirm some aid.
Also, it is wonderful that you have a plant-based diet, but if you live in USA, soil depletion from monoculture for decades is the main reason that plants which should be rich in Mg are not.
I would not mention it, as I did in my first response, unless it were a glaring defect in our agriculture.
https://www.sleepfoundation.org/magnesium
https://www.hsph.harvard.edu/nutritionsource/magnesium/#:~:text=Magnesium%20is%20a%20key%20factor,diet%20leads%20to%20health%20problems.
Thanks for the links and for your concern, the research is certainly interesting and may be something I could bring to the RLS community table. I didn’t look at all the links as I only saw them just now. I’ll do that later. However, in my particular case I have tried all sorts of supplements and found that most of them increase the RLS. I’m extremely sensitive to serotonin and believe I suffer from some kind of disorder of the serotonin metabolism, possibly SERT or DAT. Most supplements have some impact on serotonin.
I don’t live in the US and I don’t have a deficiencies, which seemed to be the indication in this research. I get a lot of these electrolytes from seeds and nuts. In fact I had an extreme amount of folate, which is suspicious and may be indicative of a problem. B6 is especially nasty in my case as it agonises serotonin. I can’t use any fortified smoothies and such. What does help is Ashwagandha (not so much RLS but other problems such as joint pain, and it doesn’t aggravate the RLS), as well as l-theanine, which I hope will continue to be helpful in the long run (I just took a long break from both green tea and theanine as I was worried about poor adenosine build up during the day). Theanine is strange as it’s not vital but does seem to calm down glutamate excitotoxicity, and presumably that’s what makes me feel amazing on it. Unfortunately I can’t get those highs on a regular regime but it does something anyway.
Thanks for your concern, however the RLS seems to be driven by my disfigured spine and the fusion surgery that’s been done to it. There may be different reasons for RLS but poor iron metabolism is the main cause usually. I also have the gene variant for this, BDBD9. It’s pure hell as I’m basically ‘allergic’ towards anything that normally calms people down so they can go to sleep. Instead these substances wake me up. That’s without ‘actually’ being allergic towards anything. So it’s a mystery that runs deeper than just RLS (in my case). I’d love to find an expert who’d understand what I’m talking about.
Evily ! (ATT: Cort also)
THANK YOU for mentioning Glutamate Excitotoxicity !!
I read something this week
-which for me-
**tied all together my 4 years of reading, searching **
first about viruses because of covid, then about CFS and Fibro because a friend has 8 conditions and I figured out they were all Vascular problems after several months.
I’m not saying the following is true–is the kernel of CFS and long covid—
Only that I strongly believe it is !
The Ischaemic Cascade.
It has about 16 stages including Glutamate Excititoxicity, and even a failure that feeds back even more glutamate.
What I am saying is that I believe that CFS et al, with their non-restorative sleep and especially PEM, have already been defined as Ischaemic Cascade.
Here is the key difference; Doctors only really seem to care about a LOCAL ischaemia– most often in the brain.
I’m talking about system-wide Ischaemia because vessels and kidneys are so substantially damaged. Or else why would heart rate be so high and not vary properly? It even takes POTS under its umbrella.
Going back 4 years:
As I learned to read research and gradually added definitions to some of the difficult terms/concepts,
I often read something and couldnt integrate it back then, but put it on a list of suspects.
Those clues were in a file, but
Glutamate Excitotoxicity was so provocative that I named an icon on my cell phone homescreen after it to not let it out of my mind.
Here is the gist and I would love, Cort, to at least draft a blog article for you to proof:
-Cort has talked about hypoperfusion and ischemia. I see hypoperfusion as the CULPRIT for quick fatigue, brain fog and emotional overload.
-We are talking about a SYSTEMIC amount of damage (see SEID, the latest name for ME)
-We thought covid was a pulmonary disease, but it is agreed now that it is systemic
Yes, all ACE2 receptors in blood vessels could be affected, but ZOOM OUT.
–Vessels are a type of SMOOTH MUSCLE organ.
All smooth muscle has ACE2 receptors. What has been noticed the most, in my synopsis since March 2020, is that Blood Vessels, the intestine and the kidneys seem consistently hardest hit.
-But the flu pandemics of the past ALSO did systemic damage to smooth muscle, only, THEY entered by Sialic Acid receptors. They too ARE ALL OVER the place in the body, including most notably: blood vessels and
intestine.
-There is a theory that leaky gut permits undigested substances into the bloodstream, and that mimicry of molecule shape can lead to a perverse autoantibody creation against a self protein — or — against a receptor.
Enter leaky brain. Zonulin is also in the BBB and multiple recent papers have stated that covid causes dysfunction of this blood brain barrier.
So what I see is that:
-there is every reason to believe in leaky BBB and not just leaky gut.
-quite likely, most of those whose problems started with perhaps leaky gut when a flu attacked its Sialic acid receptors have not yet resealed their gut
and that if the gut suspects made it leak, they too could make the BBB leak.
Bottom line:
I theorize Systemic Ischaemia– the vessels are not up to the task and need healing.
… and, as you read the 16 stages of the Ischaemic Cascade, I believe you will be saying “ya, I’ve got Exactly those symptoms”
… then we maybe have the hyperarousal culprit: Glutamate Excitotoxicity.
This Cascade accounts for
1. shallow sleep
2. reverting to anaerobic (2 ATP) metabolism when ischaemia fails to shunt enough blood to the workers (brain, muscles)
3. Post-exertional malaise because there is insufficient ATP left to clear the byproducts and to pump back OUT the Calcium pumped IN to long-term potentiate the organ.
Yes I will post a link to Ischaemic Cascade and Yes I have first line recovery strategies in mind for the blood vessels and the breached barriers.
By the way tachycardia for me is one of the signs of surplus serotonin.
Trazodone worked wonderfully for my for a couple of years, but I needed to keep increasing the dose after maybe a year on it. Now it is not enough to help me sleep, but if I don’t take it I stay incredibly awake. I’ve had to start finding other slep medicines and hope to wean off of it soon.
“Whether or not people with ME/CFS/FM have hyperarousal sleep patterns or not, CBT-I might be something worth trying given the anxiety and changes to sleep times and rhythms that accompany poor sleep in these diseases.”
I have experienced both of these–anxiety about my poor sleep, and inconsistent sleep time and rhythm. I tried sleep restriction which is a component of CBTi and found it to be brutally difficult. What helped me more was ACT using Guy Meadows’ book The Sleep Book, and Sleep School app. I also really like Yoga Nidra which I think helps with the hyperarousal. There are lots of free guided Yoga Nidra sessions out there. I like one by The StillPoint on Insight Timer. I’ve done yoga Nidra during my afternoon energy slump, at the beginning of the night to help me get to sleep, and in the middle of night if I wake up. Not all three in one day!
I’m trying to sleep drug-free at present, and while my sleep is not great these tools help. (I don’t have a prescriber at present but am looking for one as I’m willing to take meds on bad nights.)
The problem for me with sleep restriction is that it increased my anxiety about my poor sleep. There are other aspects of CBTi that I found helpful. I like the Quarter Hour Rule (QHR) which is that you get out of bed if you can’t sleep after about a quarter hour. I’ve modified it so that I may stay in bed but I do something else besides lying in bed stressing about my insomnia. There are lots of CBTi self-help books out there. I like Overcoming Insomnia by Colin Espie.
I think there is a difference between using the above tools to help manage insomnia, vs correcting the underlying problem, which I’ve not been able to do. I have ME and this hyperarousal theory makes a lot of sense to me. I can go to bed sleepy tired yet not fall asleep, but I’m not ruminating over anything at all.
I think there are some “classic” tools that help the body clock (like natural light in the late morning, avoiding caffeine etc.), but other ideas that wouldn’t work with ME/CFS. For example the idea of making yourself more tired in the evening by “getting up early regularly in the morning” would not work for my ME/CFS at all because a) sick body needs the sleep, and b) cutting sleep short in the morning causes more hyperarousal which makes me more awake the following night instead of more tired. It’s a tried and tested trick for me that getting up after only 5:15 hrs of sleep will release so much adrenaline that it will improve functionality on that day, but if I do this just one more day, I will immediatly fall ill with a cold.
I’m not worrying about drugs if they’re non-addictive (melatonine, low dose trimipramine help for me).
I agree. I also do not react normally to trying sleep rules. I could stay up all night, not nap the next day and come bedtime, I’m wired again. And if I get up early in the morning, I feel sick all day—nausea, dizziness, brain fog and tiredness. I can’t control that.
If ME patients have low morning cortisol, and trazodone substantially lowers cortisol, couldn’t it be potentially unsafe?
I’m glad that research studies are continuing to look at sleep. The TYPE of sleep may be important for any improvement of ME.
I’ve had ME since 1993. I wasn’t able to self-diagnose until much later. I was only moderately ill for a long time. Then a difficult move pushed me into the high end of the severe range.
More than 7 years later I found myself improving. The only change I had made was to shift from benzodiazepines to help me get to sleep to Seroquel (Quetiapine). I have to have something make me sleep because I have bipolar disorder, and my healthcare provider thought this would be a good thing to try.
I’m using the Seroquel every night now and getting better sleep in general. I still have a lot of ME symptoms, but my crashes don’t last as long. I feel better if I just get the rest I need. I’m not severe any longer. I’m back in the moderate range, not as functional as I was in earlier days, but overall less pain and more function.
I’m grateful for that! But I still have to be careful, of course. I can’t push, push, push without a big crash.
Thanks for these helpful definitions, Cort. In the early 2000s Dr Cheney used to rationalize a combination of drugs for sleep thus: any one of them might lead to habituation/need to increase, but a combination at very low doses would offer benefits with less risk. My spouse was helped with sleep and didn’t need to increase for several years with the Cheney combo of (1) doxepin elixir (3 mg), (2) klonepin (,5mg) and (3)Neurontin (Gabapentin) (100mg). All fractions of doses for other uses by themselves. All designed to counter hyper arousal, and lengthen restful sleep. (And yes he did like the antihistamine properties of Doxepine) He later recommended liquid Melatonin drops to be added to this mix.
Thanks Chris! Excellent recommendations. Teitelbaum also prescribes multiple sleep drugs when necessary – not sure about the doses.
Hi Cort,
Please travel up the page from here and read my response to Evily on Glutamate Excitotoxicity and please note the serendipity of my last week’s reading with her mention of “GE”.
Please especially read what I contributed and quoted on Ischaemic Cascade. To me it defines CFS with PEM and non-restorative sleep.
It’s like the phenomenon has been there all along– for brain doctors– but no one ever imagined it would be systemic through ubiquitous vessel and organ damage after pandemic-grade infection. Chris
I am a long-time veteran of |CFS and found a few key things:
1/ If it is insomnia, I always look for the reason being immune based, particularly the gut response. Foods that may have set off the immune response.
1a/ I can check that theory by doing some Benadryl which is an antihistamine. That may solve it.
1b/ Usually, the histamine response/insomnia is due to low levels of methionine (amino acid). I don’t hyper dose on it, but some low doses of 500 to 1000mg does the trick. Don’t forget that amino acid metabolism is dependent on certain B vitamins.
2/ GABA Sublingual is a miracle worker in most cases. Note this is sublingual and not via the oral route.
3/ I always suspect low levels of either calcium or magnesium.
4/ Valerian or Lemon Balm are good relaxers.
As promised,
here is a link to the stages of Ischaemic Cascade
https://en.m.wikipedia.org/wiki/Ischemic_cascade
Yes, it is wikipedia and not PubMed, but today many experts agree that they can get their info out there right away, rather than have it one-year behind the times after waiting for peer review.
But I read PubMed, Elsevior, Springerlinks etc, because one-stop shopping is not wise. And I do not find that such topics are misdefined on wikipedia. I find them all consistent.
“The ischemic cascade usually goes on for two to three hours but can last for days, even after normal blood flow returns.[3]”
I will provide you with the stages as , I guess, a teaser for you to read the article. My 2cents are in [square brackets]
1. Low blood supply decreases amount of oxygen that reaches tissues, leading to hypoxia
[but think of this happening system-wide to brain and muscles at simul.]
2. Deficiency of oxygen causes the neuron’s normal process for making ATP for energy to fail.
[they are focusing on only brain neurons but…]
3. The cell switches to anaerobic metabolism, producing lactic acid.
4. ATP-reliant ion transport pumps fail, causing the cell to become depolarized, allowing ions, including calcium (Ca?+), to flow into the cell.
5. The ion pumps can no longer transport calcium out of the cell, and intracellular calcium levels get too high.
6. The presence of calcium triggers the release of the excitatory amino acid neurotransmitter [***] glutamate.
7. Glutamate stimulates AMPA receptors and Ca2+-permeable NMDA receptors, [****] which open to allow ***more calcium into cells.
8. Excess calcium entry ***overexcites cells and causes the generation of harmful chemicals like free radicals, reactive oxygen species and calcium-dependent enzymes such as calpain, endonucleases, ATPases, and phospholipases in a process called excitotoxicity.[5][6] Calcium can also cause the release of more glutamate.
9. As the cell’s membrane is broken down by phospholipases, it becomes more permeable, and more ions and harmful chemicals flow into the cell.
10. Mitochondria break down, releasing toxins and apoptotic factors into the cell.
11. The caspase-dependent apoptosis cascade is initiated, causing cells to “commit suicide.”
12. If the cell dies through necrosis, [***] it releases **glutamate and toxic chemicals into the environment around it. Toxins poison nearby neurons, and glutamate can overexcite them.
13. If and when the brain is reperfused, a number of factors lead to reperfusion injury.
14. An inflammatory response is mounted, and phagocytic cells engulf damaged but still viable tissue.
[EXTREMELY IMPORTANT]
15. Harmful chemicals damage the blood–brain barrier.
[.]
[ I can’t speak to #16 and it may not be relevant]…
16. Cerebral edema (swelling of the brain) occurs due to leakage of large molecules like albumins from blood vessels through the damaged blood brain barrier. These large molecules pull water into the brain tissue after them by osmosis. This “vasogenic edema” causes compression of and damage to brain tissue (Freye 2011; Acquired Mitochondropathy