October 28, 2017

Email correspondence with my health care provider.

Hello, <medicine person>.

I finally managed to get my blood drawn the other day. It ended up taking an all-nighter rather than an early awakening, as that is generally a more productive state.

However, I would like to premise the results by saying that my nutritional status is not necessarily upstream of my insomnia. Indeed, the converse may be true. As general statements, not necessarily a claim about my case in particular, sleep can influence the absorption, distribution kinetics, and metabolism of nutrients.

For starters, sleep deprivation can lead to IBS via inflammation. Additionally, a single night of sleep deprivation can cut the antibody response to immunization in half. Likewise, sleep after immunization enhances immunological memory. Given that most of the immune system is located in the gut, this will indubitably have an impact on the gut microbiota. What's more, a single night of partial sleep deprivation causes insulin resistance in healthy subjects and, while I'm not well versed on the matter, insulin influences other nutrients besides glucose.

Additionally, I've previously explored the possibility that vitamin B3 (niacin) depletion caused by sleep deprivation was my problem. While my experience is consistent with B3 depletion causing dermatitis, supplementation has not yielded normalised sleep. However, B3 (as nicotinic acid) in the treatment of my acral dermatitis (mostly around the nose) is plausibly "the chicken soup fallacy" (a reference to an example brought up in my critical thinking class). That is to say, It may have gotten better anyway, regardless of B3.

Clearly, all these problems caused by sleep deprivation will lead to further sleep disruption, creating a positive feedback loop. I therefore put forward that, regardless of my nutritional outcome, we should continue to target sleep directly in addition to any other protocol.

Other updates: I have still not experienced any significant headaches since taking hydroxyzine (perhaps one or two minor ones). The evidence is mounting that hydroxyzine is the causal factor in headache cessation. I used to get headaches regularly. The majority were minor but irritating, lasting all day in an in-and-out and throbbing fashion. A few were interruptfully painful, like a pulse against a blade. Any minor headache I've experienced while taking hydroxyzine have been few and far between, mellow, and steady. I've still only learned the very basics of headaches, and I've speculated that my previous headaches were one of the vascular types, whereas my current ones are clearly the more common type; tension headaches. There are an absurd number of headache classifications, and I only know the two broad categories (vascular and tension headaches), a bit about their symptoms, a few classic examples (e.g. illness headaches and migraines), and a bit about the causal pathways (e.g location of nociceptors).

Hydroxyzine seems to have lost its subjective sedating capacities, but I would like to keep taking it for headache relief. I have still not experienced any side effect. Subjectively, I don't really notice it at all. However, there is every scientific indication that it improves objective measures of sleep (e.g. SWS/deep sleep). Indeed, it it quite plausible, if not likely, that hydroxyzine has solved my headaches precisely because of improved objective sleep. I've previously covered the causal role of sleep disruption in pain, fatigue, and cognition in this blog post.

I am interested in discussing and trying out a drug I've been interested in since its medical adoption. Namely, the orexin antagonist suvorexant (trade name Belsomra). This is a very direct way to target the sleep-wake system as compared to, say, benzodiazepines and non-benzodiazepines (Z-drugs), which target wake and sleep systems indiscriminately.


Edit: response 1, to family member.

Hey, <family member>.

Aye. I pride myself on my eloquence. Though, at times, I can get a bit wordy and/or esoteric. It also takes quite a bit of time fact checking and citing sources (even though the majority of the time my medical memory is accurate to begin with). It has the benefit, however, of being postable to my blog (which, in this case, I have utilised). I often see medical articles labelled as email correspondence.

I do not share your concerns about Belsomra's side effects. Several of the side effects are shared with the likes of ambien (i.e. sleepwalking, amnesia), and some may be an unmasking of already present sleep disorders rather than a direct cause. Additionally, its side effects don't appear to cause any significant dissatisfaction: "The incidence of discontinuation due to adverse reactions for patients treated with 15 mg or 20 mg of BELSOMRA was 3% compared to 5% for placebo. No individual adverse reaction led to discontinuation at an incidence ≥ 1%", (source). I don't think that I'm personally high risk for upper respiratory tract infection. Personally, I'm never really concerned about side effects like diarrhoea and constipation, as my normal soluble fiber intake is such that diarrhoea is effectively impossible, and constipation (not a side effect of Belsomra) is unlikely to occur and is easily treatable with osmolytes (such as high dose vitamin C, which may also have the benefit of lowering lead levels).

My main concern with suvorexant is limited efficacy. From Wikipedia, "The most common complaint about the drug is from users who report that it did not help them to sleep", (link).

I'm also sceptical that sublingual administration would provide much benefit (though, due the the relative of ease trying it, I might as well give it a shot). There are three reasons I think this. One, suvorexant has decent bioavailability (82%). Two, it has a long half life (12 hours), which means both that first-pass metabolism will be minimal, and that sublingual use will not provide significant reductions in duration of action nor increase in peak plasma levels. And three, I personally don't mind taking it a couple hours before bed (maybe 1.5 hours before bed to ensure that sleepiness continues to increase while I wait through my sleep onset latency), which also seems a more appropriate time to dose my other things (e.g. for a melatonin timing more appropriate for delayed sleep phase syndrome), making it slightly more convenient.

August 29, 2017

The case for high dose hydroxyzine for sleep.

/SIGNS AND SYMPTOMS/ In general, overdosage of hydroxyzine may be expected to produce effects that are extensions of common adverse reactions; excessive sedation has been the principal effect reported. Hypotension, although rare, may also occur.

[American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 2630] **PEER REVIEWED**
", (1).
Given this information, it seems likely that very high doses of hydroxyzine would be appropriate for insomnia. The primary side effect of hydroxyzine is one of therapeutic value.

At 400 mg per day, hydroxyzine has been found effective for anxiety, (2). Patient drop out rate do to side effects was high and, given that sedation was the chief side effect, this is evidence for its effectiveness for insomnia. However, some subjects reported mild, as opposed to marked, sedation. Therefore, it's plausible that higher doses could be required by some people. Nevertheless, if 400 mg is administered in a single dose at night then peak values, and thus effectiveness, should be greater.

Tolerance to the sedating effects of antihistamines develop rapidly, with complete tolerance to sedation from diphenhydramine (benadryl) occurring on the fourth day of twice daily administration, (3). Three times daily administration results in complete tolerance on the third day, (4). However, antihistamines increase slow wave sleep (SWSAKA deep sleep) in mice, rats, and guinea pigs, (5,6). Expectedly, this results in long lasting rebound wakefulness, (6). Therefore, it is not clear whether tolerance to antihistamine sedation per se develops rapidly, or apparent tolerance is simply sleep surplus. In any case, this insures that daytime sedation is unlikely after a few days of use for insomnia.
Regardless, hydroxyzine is also a 5-HT2A antagonist. In addition to improving sleep architecture,  5-HT2A antagonists are appealing because they lack tolerance, generally displaying reverse tolerance instead, (7,8).

Most antihistamines have anticholinergic side effects. While low acetylcholine is important during SWS, high levels are important for REM sleep, (9). For this reason, diphenhydramine reduces REM sleep, while less anticholinergic antihistamines (i.e. ketotifen) do not, (10). Hydroxyzine has comparatively insignificant anticholinergic effects, (11).

Hydroxyzine in doses up to 100 mg is able to improve sleep in PTSD, (12). However, 1 mg/kg (or about 70 mg for a normal adult) hydroxyzine to children is not as efficacious as 50 mg/kg chloral hydrate, (13). Nevertheless, melatonin plus 1.5 mg/kg hydroxyzine is able to reduce the need to take chloral hydrate from 37.1% to 6.7% in children undergoing EEG analysis, (14). Anecdotes had interested me in the 200-300 mg dose range. The study referenced above (2) makes me think that 400 mg may be adequate for most people, but not for everyone. I've been taking 150 mg hydroxyzine nightly for several weeks (Blog post) and have found it somewhat helpful, yet generally inadequate. I would like to try 300-400 mg.

(2) Rickels, K., Gordon, P. E., Zamostien, B. B., Case, W., Hutchison, J., & Chung, H. (1970). Hydroxyzine and chlordiazepoxide in anxious neurotic outpatients: A collaborative controlled study. Comprehensive psychiatry11(5), 457-474. AbstractSci-hub

(3) Richardson, G. S., Roehrs, T. A., Rosenthal, L., Koshorek, G., & Roth, T. (2002). Tolerance to daytime sedative effects of H1 antihistamines. Journal of clinical psychopharmacology22(5), 511-515.

(4) Schweitzer, P. K., Muehlbach, M. J., & Welsh, J. K. (1994). Sleepiness and performance during three-day administration of cetirizine or diphenhydramine. Journal of allergy and clinical immunology94(4), 716-724.

(5) Lin, J. S., Sergeeva, O. A., & Haas, H. L. (2011). Histamine H3 receptors and sleep-wake regulation. Journal of Pharmacology and Experimental Therapeutics336(1), 17-23.

(6) Ikeda-Sagara, M., Ozaki, T., Shahid, M., Morioka, E., Wada, K., Honda, K., … Ikeda, M. (2012). Induction of prolonged, continuous slow-wave sleep by blocking cerebral H1 histamine receptors in rats. British Journal of Pharmacology, 165(1), 167–182. http://doi.org/10.1111/j.1476-5381.2011.01547.x

(7) Vanover, K. E., & Davis, R. E. (2010). Role of 5-HT2A receptor antagonists in the treatment of insomnia. Nature and Science of Sleep, 2, 139–150.

(8) Yadav, P. N., Kroeze, W. K., Farrell, M. S., & Roth, B. L. (2011). Antagonist Functional Selectivity: 5-HT2A Serotonin Receptor Antagonists Differentially Regulate 5-HT2A Receptor Protein Level In Vivo. The Journal of Pharmacology and Experimental Therapeutics, 339(1), 99–105.

(9) Gais, S., & Born, J. (2004). Low acetylcholine during slow-wave sleep is critical for declarative memory consolidation. Proceedings of the National Academy of Sciences, 101(7), 2140-2144.

(10) Katayose, Y., Aritake, S., Kitamura, S., Enomoto, M., Hida, A., Takahashi, K., & Mishima, K. (2012). Carryover effect on next‐day sleepiness and psychomotor performance of nighttime administered antihistaminic drugs: a randomized controlled trial. Human Psychopharmacology: Clinical and Experimental, 27(4), 428-436. Sci-hub

(11) Kubo, N., SHIRAKAWA, O., KUNO, T., & TANAKA, C. (1987). Antimuscarinic effects of antihistamines: quantitative evaluation by receptor-binding assay. The Japanese Journal of Pharmacology, 43(3), 277-282.

(12) Ahmadpanah, M., Sabzeiee, P., Hosseini, S. M., Torabian, S., Haghighi, M., Jahangard, L., ... & Brand, S. (2014). Comparing the effect of prazosin and hydroxyzine on sleep quality in patients suffering from posttraumatic stress disorder. Neuropsychobiology69(4), 235-242.

(13) Sezer, T., & Alehan, F. (2013). Chloral hydrate versus hydroxyzine HCL for sedation prior to pediatric sleep EEG recording. International Journal of Neuroscience123(10), 719-723.

(14) Dirani, M., Nasreddine, W., Melhem, J., Arabi, M., & Beydoun, A. (2017). Efficacy of the sequential administration of melatonin, hydroxyzine, and chloral hydrate for recording sleep EEGs in children. Clinical EEG and neuroscience48(1), 41-47.

August 8, 2017

Pre-paper report on the basics of diabetes and insulin resistance.

I just wrote a youtube comment about diabetes and realized that I haven't yet made a compilation on it. Here, then, is a taste. Diabetes is caused by fatty molecules that infiltrate muscle and other cells and interfere with the function of insulin. In particular, ceramides, a fatty molecule, is the prime culprit for insulin resistance. However, not all fats are equally suspect. Long-chain saturated fatty acids (LCSFAs) induce acute (rapid) postprandial (after meal) insulin resistance. Long term, the claim holds true, but studies need good controls since exercise and weight loss can, at least partially, burn off the problematic molecules. I will have to discuss the pathogenesis of diabetes at a later date. For now, here are some controlled trials.

Type 1 diabetics in a crossover design, when given identical carbohydrates and protein content, saturated fat results in needing to inject more insulin AND having greater glucose levels. This is strong clinical evidence that not only supports the link between saturated fat and diabetes, but demonstrates that a single meal containing saturated fat results in postprandial insulin resistance. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609492/
Increased insulin was also found in healthy post-menopausal women, but the insulin spike was dramatic enough to prevent excessive hyperglycemia. Control groups were unsaturated fat. https://www.ncbi.nlm.nih.gov/pubmed/12493085
The same was found for non-insulin-dependent diabetes. Butter increased insulin spike, but olive oil did not. https://www.ncbi.nlm.nih.gov/pubmed/8561067

Likewise, a meta analysis of randomized controlled trials found that replacing animal protein with plant protein improved glycemic control in diabetics. http://www.mdpi.com/20726643/7/12/5509/htm

I have mechanistic and other data available. My research notes on saturated fat can be found here (does not include all research I've done, but a good chunk of it).

August 2, 2017

The case for a new sleep parameter; parasympathetic tone. (ME/CFS, POTS, and HRV)


Classic sleep parameters involve several sleep stages. These stages are identifiable via their unique brainwave patterns. Namely, rapid eye movement sleep (REM sleep), light sleep (stage 1 and 2 sleep), and deep sleep (stage 3, previously divided into stages 3 and 4). Stages 1-3 are also grouped as non-REM sleep (NREM sleep). The time spent in, and distribution of, each sleep type during the night is known as sleep architecture (not elaborated in this paper). Sleep architecture is the classical measure of objective sleep parameters.

For the purposes of this paper, I will be writing mostly about deep sleep (stage 3). Deep sleep, also known as slow wave sleep (SWS), is characterized by slow, delta waves. These are long, lazy waves that are a result of a large number of neurons firing synchronously. Additionally, the brains waste clearance system, the glymphatic system, is active during deep sleep.


Each sleep stage has been linked to specific cognitive functions. What's more, manipulating brainwaves can alter cognitive functions. For example, using a polysomnographic brain-computer interface to precisely time audio pulses to enhance slow wave amplitude can enhance memory consolidation compared to both no audio and mistimed audio, (1).

However, there is a sleep parameter that I think has been largely neglected; autonomic tone. The autonomic nervous system (ANS) consists of the sympathetic nervous system (SNS) and the parasympathetic nervous system (PSNS). While the SNS is characterized by "fight or flight" functions, the PSNS is characterized by "rest and digest" functions. By extension, it is reasonable to predict that the PSNS plays a role in sleep. Likewise, it would be expected that SNS activation would disrupt sleep.

Indeed, incorporating a measure of autonomic tone (namely, heart rate variability) can radically increase the predictive power of memory consolidation during sleep compared to brainwaves alone, (2). Heart rate variability (HRV) is a measure of change in heart rate from beat to beat. The heart rate changes rhythmically through the breathing cycle; increasing during inhalation and decreasing during exhalation. Since the heart rate is controlled by the ANS, heart rate and heart electrical parameters can be used as a measure of SNS and PSNS activation. High HRV indicates high parasympathetic tone.

One disease that is associated with by autonomic dysfunction and has an obvious connection to sleep is chronic fatigue syndrome (CFS). CFS is characterized by extreme fatigue, malaise (particularly post-exertional malaise), and unrefreshing sleep. What's more, CFS is associated with pain such as sore throat, headaches, and fibromyalgia (FM; translates to muscle pain). In fact, CFS is also called myalgic encephalitis (ME), which translates to muscle pain (myalgic) and brain inflammation (encephalitis). The condition is often referred to as "ME/CFS". All of these symptoms, as I will argue, can be explained by disrupted sleep. Specifically, disrupted deep sleep.

Sustained SWS disruption results in pain. Experimentally, disrupting SWS causes muscle pain, (3,4). Likewise, sensitivity to pain in general is increased, (5-8). Recovery sleep restores pain sensitivity, (5,9). Therefore, we would expect to find disrupted sleep in ME/CFS. Indeed, that is exactly what we find, (6,10-12). In particular, we find that alpha waves intrude into NREM sleep, including the delta waves of SWS, (6,10,11,13). However, this feature is not exclusive to ME/CFS. For example, it can also be found in rheumatoid arthritis and depression, (6,14,15).

Even though its possible to identify ME/CFS from brainwave patterns, it is, as I will argue, a downstream symptom of autonomic tone. ME/CFS patients can present with other sleep disorders in absence of alpha intrusions, (6,16-18). Thus, alpha intrusions are neither sufficient nor necessary for ME/CFS. Alpha intrusions can, nevertheless, be a marker. However, reduced HRV is a much better predictor, (18-22). This cardiac parameter indicates a decrease in parasympathetic tone and an increase in sympathetic tone.

The cause of reduced HRV in ME/CFS appears to be reduced blood volume and/or small heart syndrome, (23-26). On the face of it, reduced blood volume should result in the appearance of a smaller heart via reduced cardiac filling. However, the heart could still actually be smaller. In either case, the result is the same; reduced stroke volume (blood pumped per heartbeat) and reduced cardiac index. This necessitates an increase in sympathetic tone and decrease in parasympathetic tone in order to maintain blood pressure. Indeed, the absence of hypertension (high blood pressure) despite the autonomic shift in ME/CFS can, in and of itself, be used as an argument for reduced stroke volume. Stroke volume itself correlates with fatigue even in healthy subjects, (27).

The downstream effects of this results in several interesting downstream markers. For example, reduced blood pressure variability, elevated diastolic blood pressure during sleep, and hypotension (low blood pressure) during a tilt-table test, (20,28,29). Additionally, ME/CFS is associated with either orthostatic (standing upright) hypotension, or orthostatic tachycardia (accelerated heart rate), (30-32). Postural orthostatic tachycardia syndrome (POTS) is a condition where there is an excessive increase in heart rate while standing up. This is the result of reduced preload and stroke volume because blood that is attempting to return to the heart is being pulled to the lower part of the body by gravity. Naturally, the increased heart rate is for maintaining blood pressure, and failure to increase heart rate results in hypotension, (29,30). Reduced pulse pressure can also be observed, (31).


ME/CFS is a sleep disorder that ultimately appears to be a result of a shift towards increased sympathetic tone and decreased parasympathetic tone. This, in turn,  is the result of reduced stroke volume. Note, however, that the sympathetic nervous system increases stroke volume, so the specific claim is that ME/CFS patients have reduced stroke volume proportional to their sympathetic tone, not necessarily reduced absolute stroke volume (though absolute reductions might also be expected).

Convergent evidence indicates that autonomic activity is important in sleep. Autonomic activity is both an independent sleep parameter and a cause of disrupted sleep architecture/microarchitecture. In particular, HRV is a good independent marker of sleep quality.

Additional notes

Brain inflammation in ME/CFS is easily explained by impairment of sleep's waste clearance. However, given how recently the glymphatic system was discovered, I'm not aware of any research directly linking them. Nevertheless, anesthetics that produce slow waves also activate the glymphatic system, (33). Therefore, it is reasonable to surmise that alpha intrusions would impair glymphatic function and lead to downstream inflammation.

At least one analysis attempts to refute the relevance of alpha intrusions into delta waves, (34). It said that there is often confusion between tonic and phasic alpha frequency activity patterns. However, the remainder of their expertise is invalidated when they claim that the brain is the only organ that is affected by sleep. Given immense amounts of research, this is an absurd claim. In fact, one would be hard pressed to find an organ that isn't affected by sleep, especially if we count indirect factors. Insulin resistance, for example, is an experimentally inducible result of sleep deprivation that directly impacts muscle.

I discluded two interventional studies that are less consistent with SWS deprivation increasing pain, (35,36). One suggests an associated between SWS and sleep duration, so the results may be due to recovery sleep, (35). The other did suggest an insignificant lowered pain thresholds in the morning in the experimental group, (36). Given the short duration of these studies, the outcome will be dramatically affected by the state of the subjects coming into the study (e.g. sleep debt). Since false negatives are easier than false positives in statistics (via relatively poor controls and/or high population variability), these are not sufficient evidence against the claim.

I'm now on Patreon. If one benefits from my efforts, one might consider donating. :)


(1) Bellesi, M., Riedner, B. A., Garcia-Molina, G. N., Cirelli, C., & Tononi, G. (2014). Enhancement of sleep slow waves: underlying mechanisms and practical consequences. Frontiers in Systems Neuroscience, 8, 208. http://doi.org/10.3389/fnsys.2014.00208

(2) Whitehurst, L. N., Cellini, N., McDevitt, E. A., Duggan, K. A., & Mednick, S. C. (2016). Autonomic activity during sleep predicts memory consolidation in humans. Proceedings of the National Academy of Sciences of the United States of America, 113(26), 7272–7277. http://doi.org/10.1073/pnas.1518202113

(3) Moldofsky, H., & Scarisbrick, P. (1976). Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation. Psychosomatic medicine, 38(1), 35-44. https://www.ncbi.nlm.nih.gov/pubmed/176677

(4) Lentz, M. J., Landis, C. A., Rothermel, J., & Shaver, J. L. (1999). Effects of selective slow wave sleep disruption on musculoskeletal pain and fatigue in middle aged women. The Journal of rheumatology, 26(7), 1586-1592.

(5) Onen, S. H., Alloui, A., Gross, A., Eschallier, A., & Dubray, C. (2001). The effects of total sleep deprivation, selective sleep interruption and sleep recovery on pain tolerance thresholds in healthy subjects. Journal of sleep research, 10(1), 35-42.

(6) Drewes, A. M. (1999). Pain and sleep disturbances with special reference to fibromyalgia and rheumatoid arthritis. Rheumatology, 38(11), 1035-1038. https://doi.org/10.1093/rheumatology/38.11.1035

(7) Irwin, M. R., Olmstead, R., Carrillo, C., Sadeghi, N., FitzGerald, J. D., Ranganath, V. K., & Nicassio, P. M. (2012). Sleep Loss Exacerbates Fatigue, Depression, and Pain in Rheumatoid Arthritis. Sleep, 35(4), 537–543. http://doi.org/10.5665/sleep.1742

(8) Finan, P. H., Goodin, B. R., & Smith, M. T. (2013). The association of sleep and pain: An update and a path forward. The Journal of Pain : Official Journal of the American Pain Society, 14(12), 1539–1552. http://doi.org/10.1016/j.jpain.2013.08.007

(9) Faraut, B., Léger, D., Medkour, T., Dubois, A., Bayon, V., Chennaoui, M., & Perrot, S. (2015). Napping Reverses Increased Pain Sensitivity Due to Sleep Restriction. PLoS ONE, 10(2), e0117425. http://doi.org/10.1371/journal.pone.0117425

(10) Moldofsky, H., & Lue, F. A. (1980). The relationship of alpha and delta EEG frequencies to pain and mood in ‘fibrositis’ patients treated with chlorpromazine and L-tryptophan. Electroencephalography and clinical neurophysiology, 50(1), 71-80.

(11) Branco, J., Atalaia, A., & Paiva, T. (1994). Sleep cycles and alpha-delta sleep in fibromyalgia syndrome. The Journal of rheumatology, 21(6), 1113-1117.

(12) Keskindag, B., & Karaaziz, M. (2017). The association between pain and sleep in fibromyalgia. Saudi Medical Journal, 38(5), 465–475. http://doi.org/10.15537/smj.2017.5.17864

(13) Perlis, M. L., Giles, D. E., Bootzin, R. R., Dikman, Z. V., Fleming, G. M., Drummond, S. P., & Rose, M. W. (1997). Alpha sleep and information processing, perception of sleep, pain, and arousability in fibromyalgia. International Journal of Neuroscience, 89(3-4), 265-280.

(14) Drewes, A. M., Svendsen, L., Taagholt, S. J., Bjerregård, K., Nielsen, K. D., & Hansen, B. (1998). Sleep in rheumatoid arthritis: a comparison with healthy subjects and studies of sleep/wake interactions. British journal of rheumatology, 37(1), 71-81. https://doi.org/10.1093/rheumatology/37.1.71

(15) Jaimchariyatam, N., Rodriguez, C. L., & Budur, K. (2011). Prevalence and Correlates of Alpha-Delta Sleep in Major Depressive Disorders. Innovations in Clinical Neuroscience, 8(7), 35–49.

(16) Manu, P., Lane, T. J., Matthews, D. A., Castriotta, R. J., Watson, R. K., & Abeles, M. (1994). Alpha-delta sleep in patients with a chief complaint of chronic fatigue. Southern medical journal, 87(4), 465-470.

(17) Carette, S., Oakson, G., Guimont, C., & Steriade, M. (1995). Sleep electroencephalography and the clinical response to amitriptyline in patients with fibromyalgia. Arthritis & Rheumatology, 38(9), 1211-1217.

(18) Chervin, R. D., Teodorescu, M., Kushwaha, R., Deline, A. M., Brucksch, C. B., Ribbens-Grimm, C., … Crofford, L. J. (2009). OBJECTIVE MEASURES OF DISORDERED SLEEP IN FIBROMYALGIA. The Journal of Rheumatology, 36(9), 2009–2016. http://doi.org/10.3899/jrheum.090051
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909463/ (free full text. Not final version?)

(19) Beaumont, A., Burton, A. R., Lemon, J., Bennett, B. K., Lloyd, A., & Vollmer-Conna, U. (2012). Reduced Cardiac Vagal Modulation Impacts on Cognitive Performance in Chronic Fatigue Syndrome. PLoS ONE, 7(11), e49518. http://doi.org/10.1371/journal.pone.0049518

(20) Frith, J., Zalewski, P., Klawe, J. J., Pairman, J., Bitner, A., Tafil-Klawe, M., & Newton, J. L. (2012). Impaired blood pressure variability in chronic fatigue syndrome—a potential biomarker. QJM: An International Journal of Medicine, 105(9), 831-838.

(21) Rahman, K., Burton, A., Galbraith, S., Lloyd, A., & Vollmer-Conna, U. (2011). Sleep-Wake Behavior in Chronic Fatigue Syndrome. Sleep, 34(5), 671–678. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3079947/ (free full text)

(22) Naschitz, J. E., Slobodin, G., Sharif, D., Fields, M., Isseroff, H., Sabo, E., & Rosner, I. (2008). Electrocardiographic QT interval and cardiovascular reactivity in fibromyalgia differ from chronic fatigue syndrome. European journal of internal medicine, 19(3), 187-191.

(23) Newton, J. L., Finkelmeyer, A., Petrides, G., Frith, J., Hodgson, T., Maclachlan, L., ... & Blamire, A. M. (2016). Reduced cardiac volumes in chronic fatigue syndrome associate with plasma volume but not length of disease: a cohort study. Open heart, 3(1), e000381. http://dx.doi.org/10.1136/openhrt-2015-000381

(24) Streeten, D. H., & BellMD, D. S. (1998). Circulating blood volume in chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 4(1), 3-11.

(25) Miwa, K., & Fujita, M. (2008). Small heart syndrome in patients with chronic fatigue syndrome. Clinical cardiology, 31(7), 328-333.

(26) Miwa, K., & Fujita, M. (2009). Cardiac function fluctuates during exacerbation and remission in young adults with chronic fatigue syndrome and “small heart”. Journal of cardiology, 54(1), 29-35. https://doi.org/10.1016/j.jjcc.2009.02.008 (free full text)

(27) Nelesen, R., Dar, Y., Thomas, K., & Dimsdale, J. E. (2008). The Relationship Between Fatigue and Cardiac Functioning. Archives of Internal Medicine, 168(9), 943–949. http://doi.org/10.1001/archinte.168.9.943

(28) Hurum, H., Sulheim, D., Thaulow, E., & Wyller, V. B. (2011). Elevated nocturnal blood pressure and heart rate in adolescent chronic fatigue syndrome. Acta Paediatrica, 100(2), 289-292.

(29) Rowe, P. C., Bou-Holaigah, I., Kan, J. S., & Calkins, H. (1995). Is neurally mediated hypotension an unrecognised cause of chronic fatigue?. The Lancet, 345(8950), 623-624.

(30) Rowe, P. C., Barron, D. F., Calkins, H., Maumenee, I. H., Tong, P. Y., & Geraghty, M. T. (1999). Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome. The Journal of pediatrics, 135(4), 494-499.

(31) Reynolds, G. K., Lewis, D. P., Richardson, A. M., & Lidbury, B. A. (2014). Comorbidity of postural orthostatic tachycardia syndrome and chronic fatigue syndrome in an Australian cohort. Journal of internal medicine, 275(4), 409-417.

(32) Hoad, A., Spickett, G., Elliott, J., & Newton, J. (2008). Postural orthostatic tachycardia syndrome is an under-recognized condition in chronic fatigue syndrome. QJM: An International Journal of Medicine, 101(12), 961-965.

(33) Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., … Nedergaard, M. (2013). Sleep Drives Metabolite Clearance from the Adult Brain. Science (New York, N.Y.), 342(6156), 10.1126/science.1241224. http://doi.org/10.1126/science.1241224

(34) Mahowald, M. L., & Mahowald, M. W. (2000). Nighttime sleep and daytime functioning (sleepiness and fatigue) in less well-defined chronic rheumatic diseases with particular reference to the ‘alpha-delta NREM sleep anomaly’. Sleep medicine, 1(3), 195-207.

(35) Walsh, J. K., HARTMAN, P. G., & Schweitzer, P. K. (1994). Slow‐wave sleep deprivation and waking function. Journal of sleep research, 3(1), 16-25.

(36) Older, S. A., Battafarano, D. F., Danning, C. L., Ward, J. A., Grady, E. P., Derman, S., & Russell, I. J. (1998). The effects of delta wave sleep interruption on pain thresholds and fibromyalgia-like symptoms in healthy subjects; correlations with insulin-like growth factor I. The Journal of rheumatology, 25(6), 1180-1186.

July 30, 2017

My first week on hydroxyzine.

All claims are for a nightly dose of 150 mg hydroxyzine. Melatonin (rapid release) was taken on all nights at the same time as hydroxyzine, generally at my usual melatonin dose of 150 mcg. Two nights I took 300 mcg melatonin, but I was more tired those days (possibly unrelated), so I discontinued. I will see if timed release 300 mcg melatonin tablets work better.

Objective and/or relatively falsifiable claims.
  • I've had no headaches since starting hydroxyzine, whereas I normally experience regular headaches. Insufficient data to definitively claim that hydroxyzine is the causal factor.
  • Sleep onset latency is reduced to less than 45 minutes (usually after waiting 1 hour for hydroxyzine levels to rise, making sleep onset less than 1 hour and 45 minutes post administration).
  • Earlier sleep onset is achievable. Early sleep onset usually results in early awakenings. Its possible that this issue could dissipate with time on a stable schedule.
  • Photophobia is reduced/eliminated. Insufficient data to make a proper analysis.

Subjective claims.
  • Sleep urge at peak concentrations (~2 hours) is insufficient to desire sleep.
  • Grogginess is reduced dramatically.
  • Tiredness is reduced between 2 to 10 times, depending on reference point.
  • Tiredness is extremely stable in comparison to previously, yielding very little deviation within a day.
  • Tiredness is inversely correlated with sleep quality, compared to a previously paradoxical and unstable relationship. Presumably, this may be due to a shift from a compensatory stress response to more conventional wake promoting mechanisms.
  • Inter-day subjective variable heterogeneity is reduced dramatically. There is much more homogeneity for sleep time, sleep duration sleep quality, alertness, and energy.

Preferences and wants.
I would like to continue taking hydroxyzine. However, I would like to try an increased dose. The reasons are severalfold. I would like to see if larger doses can induce sleep urge. I would also like to have the option of earlier sleep onset without worry of early awakenings. I hope that more stable and/or enhanced sleep can improve functioning and subjective states. Lastly, I would like an antihistamine tolerance to drug metabolism ratio suitable for sustained vigilance (a theoretical benefit, not necessarily accurate).

My second week on hydroxyzine (still 150 mg) has not been as successful as the first week in terms of sleep latency and sleep schedule. However, I seemed to be even less sleepy than last week. In fact, I think it was the fact that I was less sleepy that was giving me trouble sleeping. (Edit: in retrospect, I don't think it was sleep debt since I don't recall it working better after bad sleep. I think it's more likely tolerance to the antihistaminergic effects, which I was expecting, prepared for, and even counting on. I haven't quite nailed the time frame of tolerance, though given rapid tolerance to sedation from diphenhydramine/benadryl (2), I would expect to reach peak tolerance within a weak or two) Nevertheless, several differences between the two weeks need to be considered before drawing concrete conclusions. The first week I was visiting family, was woken up by their bustling (providing sleep debt to help me sleep), ate differently, and did different activities. Furthermore, this second week I tried incorporating methylxanthine (caffeine and theobromine) tolerance to enhance the effectiveness of the antihistamine. It hasn't really worked yet, but I'm discontinuing early because I think it was disrupting my sleep, and I don't particularly enjoy the acute effects.

I'll talk to my medical provider and try to convince her to give me the higher doses which I originally wanted. Namely, 200-300 mg, with my experience so far suggesting the high end might be appropriate. The highest dose I've found in a study is 400 mg daily; double a normal dose, (1). They found it effective for anxiety, but reported high incidence of sedation as a side effect. In fact, they had a high drop out rate due to "side effects". Sedation appears to be the primary reason larger doses aren't often used for anxiety. Obviously, that is not a side effect in my case. I find it absurd that they don't just try administering the drug at night.

Conclusion: 150 mg of hydroxyzine nightly has improved my subjective sleep quality dramatically. However, beyond a week of administration it failed to enhance sleep schedule or nighttime subjective tiredness. Daytime functioning remains enhanced. I wish to increase my dose to 300-400 mg. My original dose range preference (200-300 mg) was based on anecdotes. This study has me thinking that 300-400 mg may be a better range because some patients only reported mild, as opposed to marked, sedation on 400mg daily.

UPDATE 2: I've been taking the same dose for over a month now. No change from week two. I tried 200 mg for several nights (my prescription is still only 150 mg), and it seemed moderately more effective, but I didn't take that dose long enough to develop peak tolerance.

(1) http://www.sciencedirect.com/science/article/pii/0010440X70900064?via%3Dihub

(2) Tolerance to daytime sedative effects of H1 antihistamines. https://www.ncbi.nlm.nih.gov/pubmed/12352276

June 5, 2017

Perhaps blood volume insufficiency is a major cause of migraine.

"The occurrence of migraine in women is influenced by hormonal changes throughout the lifecycle. A beneficial effect of pregnancy on migraine, mainly during the last 2 trimesters, has been observed in 55 to 90% of women who are pregnant", (1). Why do two thirds of pregnant migraineurs see an improvement in symptoms? I believe it may be due to the blood volume expansion. However, I have come across a paper that has me questioning the precise mechanisms of benefits from blood volume expansion, but it still clearly seems autonomic in nature. Given that pregnancy doesn't obviously improve sleep, the mechanism for migraine improvement appears independent of sleep.
I have been sick for a few days. Headache has been one of the primary symptoms. I experience headaches regularly regardless. I almost never experience tension headaches. Interestingly, however, during my sick period my headaches were worse during orthostasis (standing). The throb was very dramatic. I could feel each heart beat precisely. My supine (lying down) heart rate was 100 bpm. I didn't measure my orthostatic heart rate. Orthostatic headaches were more persistent than supine ones. In fact, the majority of supine headaches lasted only a dozen or so heartbeats, and only initiated due to plopping down on the bed. Retrospectively, nearly all of my everyday headaches may be orthostatic. Really, I would like to see albumin infusion as an attempt to treat migraines. I would expect both sleep-dependent and sleep-independent improvements. I don't know why nobody ever looks for/at upstream disease causes.
FYI, acetaminophen (tylenol) doesn't appear to impair sleep, while NSAIDs (aspirin, ibuprofen) do.
(2) Drug-induced arterial pressure elevation is associated with arousal from NREM sleep in normal volunteers:
(3) Migraine: A Chronic Sympathetic Nervous System Disorder:

May 21, 2016

Low Blood Pressure (Hypotension), Sodium/Salt, and Sleep.

(edit: this is now out of date. I now believe that intravascular albumin may be exponentially more important than sodium, as sodium does not posses intravascular specificity. Salt also has other negative properties. Also, this post is slightly out of context regarding DSPS, but I will likely write more about DSPS at a later date)
Here is a post a made on facebook. It seems my blog is a good place to paste it as well.

TLDR: Unless you have high blood pressure, try salt for sleep or apparent Delayed Sleep Phase Syndrome (DSPS).

Hey guys. At a recent doctors appointment, I noticed my blood pressure was on the low side (90/54). A couple of months ago, my blood pressure was normal (110/90). In retrospect, I have had symptoms of hypotension (e.g. vision darkening when standing up) even though my blood pressure was measured as normal. I noted such things on the sleep questionnaire, but the doctors didn't catch it, being useless as they are. The only reason I caught it is because I was lucky enough to take note of my slightly low blood pressure.

Looking up the relationship between hypotension and insomnia, I was only able to find one study. In patients with insomnia, 1/3 had hypotension. This hypotension was associated with symptoms I recognized in myself and from this group. In particular, the paradoxical "long-lasting increased excitability" was of interest.

Additionally, sleep deprivation may raise blood pressure, perhaps masking the diagnosis. Thus, even if your blood pressure is normal during doctor visits, you may have night-time hypotension.

I was able to find an article about a study regarding sodium intake and sleep, though I can't find the original research paper. A very low sodium diet (500mg) led to night-time awakenings and less sleep, whereas this was not a problem on a 2000mg diet. What's interesting is that during high sodium diet (5000mg) there was even fewer night-time awakenings and even more sleep.

For this reason, I started adding salt to my diet a couple of days ago (about 5g iodized salt, or 2000mg sodium). This is in addition to the sodium I was already consuming, so I might be getting 3000-4000mg total. I consume potassium above the 98th percentile, which is around the RDA of 4700mg. I probably consume 5000-6000mg potassium daily. This probably exacerbated the problem, but likely isn't a problem for anyone reading this. I've had sleep problems long before upping my potassium intake, though I don't know what my sodium intake was back then. I also had regular darkening/blackened vision upon standing, thus suggesting this may have been a long term issue.

So far, though it's too soon to say for sure, I'd say It's helping. It's only my third day taking salt. Please leave a comment if any of this sounds familiar, as there appears to be little scientific data available.

I suspect many people with DSPS attempt eating healthy in hopes that it will help. This, in turn, may lower blood pressure and actually make things worse, at least for 1/3 of us. Most people consume too much sodium and not enough potassium, but that's likely not as much the case for those of us trying to compensate for chronic problems with a good diet. If any of this sounds like you, try adding salt to your diet and see if it helps.




(Edit: This data, in sleep-disordered breathing patients, with a larger sample size than the other srudy, may put the number of insomniacs with hypotension at a lower estimate, though they don't appear to measure sleeping blood pressure as the other one did. Due to the disease criteria used, it may be entirely irreverent to insomniacs (though still worth noting), or it may be that the country it was done in has higher blood pressures in general.