March 9, 2019

Glycerin Hygroscopy Values: Results From My Experiments. AKA Putting On My Nerd Pants.

This is a short deviation from my usual writings. I'm not applying my usual rigor with citations because I'm mostly citing facts that can easily be looked up.


I use vegetable glycerin (AKA glycerol) to dampen supplements so that they compact more tightly. This allows me to fit more in a smaller space, and also allows supplements to sink to the bottom of the stomach. For example, spinach powder is relatively light and fluffy. I'd estimate that I can fit 30% more spinach into a capsule if I add glycerin. Additionally, when glycerin is added it doesn't bounce back when compacted, therefore making it easier for me to fill pills to maximum capacity.

The Conundrum

"Why glycerin?", you may ask. Why not just use water? Because using water would provide a breeding ground for mold and bacteria. Thus, I use glycerin precisely because it is not water. High levels of glycerin can be used as a food additive to preserve food, much like sugar or salt. It lowers water activity, limiting the ability of microbes to grow.

Additionally, there is one other reason I'm using glycerin. Initially, I had tested both glycerin and propylene glycol, filling a vegetable cellulose capsule with each respectively. The capsule filled with propylene glycol dissolved, while the capsule filled with glycerin did not. Thus, I settled on vegetable glycerin.

However, I began to notice something strange. Over time, capsules to which I had added glycerin began to become stretched, and the outside of the capsule became wet. Glycerin is hygroscopic, meaning that it can absorb water from the air. As such, the fluid volume increased, expanding the capsule and overflowing into the container.

Therefore, I ran a second experiment. I combined glycerin with various amounts of water, and put it into capsules. I found that large amounts of water could be added without dissolving the capsule. The cellulose capsules could withstand at least 50% water, or 1 to 1 glycerin to water by weight. However, the larger quantities of water did warp the capsules slightly. Nevertheless, I ended up using a 1 to 1 ratio

But the story doesn't end there. Sure, 50% water worked, but was it optimal? I wanted to get the water activity as low as possible. I always make at least a month's supply of pills, usually 3 months' worth. Thus, the more certainty that the pills will preserve, the better. So I ran a third experiment. I put 100 grams of glycerin into an open container, labeled it, set it at the back of my desk, and forgot about it. I weighed it every so often, when the fancy struck. Months later, I put it on the scale; it weighed exactly 40 grams more than the starting weight.

Thus, my new mixture of 40 parts water per 100 parts glycerin was born. However, I still needed to confirm that this was the maximum water holding capacity of glycerin. I filled a container with 50 parts water to 100 parts glycerin to see if it would continue to increase or not. As it turns out, it decreased in weight, suggesting that water evaporated.

Final Results

OK. So we have the hygroscopic capacity of glycerin. We're reasonably confident that pills will preserve. What's missing? Details. For example, how does humidity affect the hygroscopicity of glycerin? How long does it take for glycerin to absorb water? What about alternative units, and using volume instead of weight? I've taken care of that. In a final experiment, I set up a small amount of glycerin and meticulously tracked its weight over time. I converted it to various units. Note that percent is expressed as a fraction. I also looked up humidity at time of measurement, but it didn't fit neatly on the graph. You're welcome to check out the that data in the original spreadsheet. As you can see, I could lower the water content of my recipe from 40 parts per 100 to 38 or so (as seen in orange: the weight ratio of water to glycerin)

August 29, 2018

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: namely sedation.

At 400 mg per day, hydroxyzine has been found effective for anxiety, (2). Patient drop out rate due to side effects was high; 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 than 400 mg throughout the day.

Tolerance to the sedating effects of antihistamines develops rapidly. Complete tolerance to sedation from diphenhydramine (benadryl) occurs 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 (SWS, AKA deep sleep) in mice, rats, and guinea pigs, (5,6). Expectedly, this enhanced sleep results in long lasting rebound wakefulness upon withdrawal, (6). Therefore, it is not clear whether tolerance to antihistamine sedation per se develops rapidly, or if apparent tolerance is simply a 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). That is to say, one becomes more sensitive to the effects of the drug with repeated use, as contrasted to drugs losing their effectiveness in the case of normal drug tolerance.

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 had 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 psychiatry, 11(5), 457-474. Abstract, Sci-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 psychopharmacology, 22(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 immunology, 94(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 Therapeutics, 336(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.

(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. Neuropsychobiology, 69(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 Neuroscience, 123(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 neuroscience, 48(1), 41-47.

June 16, 2018

Suffering and Death: Law and ethics presentation.

This was written form my presentation in my Law and Ethics class, delivered June 13, 2018.

Suffering and Death

Suffering is overrated. Mother Teresa saw beauty in suffering, (1, p. 11). She has likened it to a kiss from Jesus, (2). Likewise, I think that the general population holds an implicit view that is similar to this.

Death, on the other hand, is vastly underrated. Death is one of the most efficient remedies to suffering. Death is only problematic insofar as it generates suffering for those who are still alive. However, avoidance of death on these grounds is often only delaying the inevitable. Furthermore, it seems wrong to make someone suffer for ones own benefit. Insofar as this principle is agreed upon, we should strive to offer death to those in need.

Washington state does have one measly Death With Dignity Act. It is quite pathetic in scope. The act only allows death for those with 6 months or less to live, (3). Last year, lethal medication was dispensed to scant 200 patients, (3). Not all of them have taken the medication, but I find that to be ethically irrelevant. I find the fact that a patient must ask for the right to a graceful exit to be morally disgusting.

Blackstone's formulation is the principle that it is better to let ten criminals free than convict one innocent person. Our courts operate on this principle. The phrase "innocent until proven guilty" is one manifestation of this commitment. I, for one, agree with this principle as a matter of law. Naturally, in this analogy, life is the prison, and death is freedom. It is better to kill ten people than to let one suffer unwillingly. Likewise, it is better to prevent births when the baby is likely to suffer.

Schizophrenia is a genetic psychotic disorder. More specifically, it may be a genetic sleep disorder, (4). The rate of attempted suicide in schizophrenics is extremely high. The lower-bound estimate for suicide attempts among schizophrenics is 20%, (5). This 5:1 ratio fails to conform to the Blackstone ratio of 10:1. As such, this seems to be one of the more obvious cases where births should be prevented. Even sadder, many of those attempting suicide will never succeed. At the very least, schizophrenics should be given suicide drugs at the time of diagnosis.

There is a nonprofit organization called the Final Exit Network; named after the book "Final Exit." They offer information on how to commit suicide. By the bounds of law, they cannot directly assist in the suicide, but they can provide company and support. I'd certainly like to volunteer with them. However, even they are insufficient. They run each case by a team of doctors; a practice I find despicable, as it again enters the territory of asking permission. Nevertheless, it is not quite clear how much of their practice is designed to keep themselves safe from the law.

Antinatalists argue that it is unethical to have children. From a deontological perspective, their case is strong. Reproduction is a gamble with someone else's life. Nevertheless, there are other ways around this. In any case, as a utilitarian I am forced to explore alternative solutions to ending unwilling suffering.

People often ascribe value to suffering where there is none. People with pain asymbolia lack negative associations with painful stimuli. In effect, they are able to experience the sensation of pain without the associated suffering. Of course, this flies against the very notion of "pain," and will likely require a new word in the dictionary. In any case, these people can be trained to avoid damaging situations without the need to suffer. As such, suffering seems unnecessary in this regard.

Some people, such as myself, might assume that suffering is necessary for empathy. It turns out, however, that this is just an assumption without much empirical backing. People with congenital analgesia are born with a complete inability to feel physical pain. Unlike those with pain asymbolia, they'd have no way of knowing if their finger was broken without looking. Nevertheless, these people seem to have no deficit in empathizing with those in physical pain, (6).

However, humans are not the only, nor even the primary subjects to which these concerns apply. One obvious example is research animals. If death is ultimately not a big deal, can it be justified to torture animals for the sake of preventing human death?

From a deontological, rights based perspective, food animals deserve immediate extermination. The suffering imposed on farms is beyond reasonable comprehension of the human mind. We have bred entire species predicated on disease causing selections. Chickens, for example, can grow too large before there bones are developed and become crippled with arthritis.

Indeed, the scope of concern for non-human animals extends much further than that. The modern philosopher Brian Tomasik argues that Wild Animal Suffering (WAS) is unacceptable. He argues that suffering outweighs happiness in nature, and that we should reduce biomass to eliminate foodstuffs that fuel suffering. Brian Tomasik is a negative utilitarian, meaning that he only cares about reducing suffering. His arguments are so compelling that I, as a classical utilitarian, can't help but to agree. From the perspective of a negative utilitarian, total destruction of earth is an ideal solution to WAS. Even to a classical utilitarian, I'd argue that this is a reasonable solution if one doesn't believe that society will remedy the situation one day.

There is another solution that I would be remiss were I to fail to mention. The modern philosopher David Pearce argues that we should use biotechnology to abolish suffering throughout the living world. In humans, the first step is using eugenic technologies to weed out unfavorable genotypes. The aim is to upregulate the hedonic set point, such that the spectrum of experience lies well above hedonic zero. Being set on fire would merely be less pleasant than a back massage, rather than horrific. The potential of preimplantation genetic screening and genetic engineering is boundless.

Eugenics has historically received a bad name. Largely, this is a function of the utilization of negative eugenics. That is to say, we would forcefully prevent people from breeding. In contrast, positive eugenics promotes the advancement of desired genes. Furthermore, the interest of those being born is oft not considered. Selecting against depression and anxiety are moral imperatives. Whether it is ethical to sterilize depressives, schizophrenics, and the anxious is a more sensitive issue. Given my Ashkenazi ancestry, and the rate of CNS diseases among Ashkenazi Jews, it seems that I should not be allowed to procreate via natural means. What is clear is that people must be offered the chance to use biotechnology to eliminate these risks in their offspring.

In summary, the utility of death needs to be taken more seriously. Furthermore, suffering is a much neglected issue. It is unethical to force life on the suffering. Even to allow the suffering to live is ethically questionable.


1. Hitchens, C. (1995). The missionary position: Mother Teresa in theory and practice. New York: Verso
2. WHATEVER YOU DID UNTO ONE OF THE LEAST, YOU DID UNTO ME. (n.d.). Retrieved June 13, 2018, from
3. Center for Health Statistics. (2018) Death With Dignity Act Report. Retrieved June 13, 2018, from
4. D’Agostino, A., Castelnovo, A., Cavallotti, S., Casetta, C., Marcatili, M., Gambini, O., … Sarasso, S. (2018). Sleep endophenotypes of schizophrenia: slow waves and sleep spindles in unaffected first-degree relatives. NPJ Schizophrenia, 4, 2.
5. Verma, D., Srivastava, M. K., Singh, S. K., Bhatia, T., & Deshpande, S. N. (2016). Lifetime suicide intent, executive function and insight in schizophrenia and schizoaffective disorders. Schizophrenia Research, 178(1-3), 12–16.
6. Danziger N, Faillenot I, Peyron R. Can We Share a Pain We Never Felt? Neural Correlates of Empathy in Patients with Congenital Insensitivity to Pain. Neuron 61: 203–212, 2009.

November 26, 2017

The Continuing Adventures of Medical Discourse. (warning: long)

(note that parenthetical edits are to the email itself and not to the blog post):
Hello, <medicine person>.

I remain interested in trying high dose hydroxyzine for sleep. We have not yet exhausted my original dose-range of interest. Additionally, much of the loss of efficacy occurred after you switched me to the pamoate form. Whether this has played a role in reduced effectiveness is uncertain, but I would like to test it out by going back to the hydrochloric form. (edit: I have since got the hydrochloric form since the prescription is apparently still valid. It doesn't appear any more noticeable than pamoate when the dose of either form is 150mg)

So far, you have only prescribed me the very lowest of my dose-range requested. Namely, 200mg. My initial interest was 200-300mg, but was updated to 300-400mg after trial of 150mg, and seeing a study using 400mg. This remains the dose range wherein my curiosity lies. Indeed, my interest stretches beyond such doses, but I would not ask for an untested dose from a medical professional.

Due to the limited efficacy, I have restarted a methylxanthine regimen (caffeine and theobromine) in attempt to increase the efficacy of antihistamines via histaminergic tolerance (both directly and indirectly downstream of adenosine antagonism). As is often the case when I try methylxanthines, due to unsatisfactory efficacy, my dose increases 'till the tolerable limit is reached. Vomiting ensues, as has happened roughly half a dozen times before. I think that acceptable side effects can be a good indication of the severity of a condition, whereas outward appearance is often utterly useless (or, as in my case, counterproductive given paradoxical states). Personally, I would be willing to accept several hours of nausea and vomiting daily if it could guarantee me relief the remainder of the day (obviously, this is not a trade-off I actually have available to me).

My current methylxanthine dose has remained stable for a short while at 384mg caffeine and 384mg theobromine daily divided in several doses (paired with 768mg L-theanine to take the edge off). Sometimes I add one 128mg/128mg/256mg dose later in the day. This is roughly the upper tolerable limit (UTL). Increasing it by about 33-50% (I'd say 33% for a dose and 50% for a day) yields nausea and vomiting. The reasons my dose migrates towards the UTL are twofold. The first is that I experience minimal, if any, wake promotion from these drugs/supplements. The second is that I desire to develop as much of a tolerance as possible, so as to become more sleepy at night. (edit: I have since lowered my dose a bit)

It has seemed that tolerance to this dose of methylxanthines has increased the efficacy of hydroxyzine. I seem able to achieve irresistible sleep urge at night (it is worth noting that this does not appear to coincide consistently with peak plasma levels of hydroxyzine). However, I am endlessly exhausted. Therefore, the mechanism of efficacy is dubious.

In summary, I would like to try, say, 350mg of hydroxyzine. This seems to be a reasonable dose given the research. Since I don't experience any side effects, there is nothing in particular that I can think of which would indicate any sort of upper limit. In any case, whatever dose of hydroxyzine required is likely safer than whatever else I might try out of desperation (e.g. caffeine megadose tolerance formation).

Response from family member:
Hello Lysander,

Thank you for the update on your biochemistry / sleep research.

One thought on reading through your review: you said that even though you seem able to achieve "irresistible sleep urge" you are still "endlessly exhausted".

It could be very possible that the "endless exhaustion" is NOT from sleep deprivation. I have seen many symptom histories from people and indeed, have experienced it myself, that endless exhaustion can and often is independent from sleep duration or quality and has it's origins in an entirely different mechanism.

My reply: 
Thanks for the input, <family member>.

To clarify a bit, the endless exhaustion is a reference specifically to my experience during methylxanthine use compared to baseline. While the descriptor could certainty be used to articulate my general state, that instance was talking about my state as compared to baseline.

As for statement that "exhaustion can and often is independent from sleep duration or quality", I think that that is a reasonable position to hold, and could be supported, but I don't personally believe it's generally possible. Hypersomniacs arguably have more and better sleep, but given that I don't think that EEG parameters are the whole story, I think it's just as plausible that other forms of sleep impairment are causing compensatory EEG parameters downstream of reduced sleep quality. Nevertheless, you are correct that the upstream cause may indeed have nothing to do with impaired sleep per se, and that it's at least theoretically possible to maintain exhaustion and/or sleepiness in spite of surplus sleep.

I would be interested in hearing some anecdotes on the matter. I doubt that it would change my opinion that sleep is the ultimate issue, but it could certainly sway me to thinking that improving sleep directly is a poor choice of action.

Response from medical provider:

Have finally received all the lab work back regarding your condition - - first tings first,  yes, trial increasing the Hydroxyzine (you might have already, though you have the official okay).

And after reviewing much of the lab work, here are some very initial findings:

Edit: for brevity, the following is my summary of what she wrote.
Free T3 4.98 pg/ml (+ 346 %)
Thyroglobulin Abs 3.00 IU/ml (+ 250 %)
TSH 5.25 µU/mL (+ 182 %)

She speculated that I might have Graves disease, and suggested we test for it. She listed the symptoms, highlighted mine among them (at least, her view of my symtoms). Namely, fatigue, general weakness, palpitations, and insomnia. I disconcur with some of these to varying extents.

She also said she has to review the data more.

My response

When discussing hyperthyroidism in relation to insomnia, I think that it's important to note that supraphysiological doses of levothyroxine given to healthy subjects does not significantly alter sleep architecture when administered in an open-label fashion. In my opinion, this shifts the burden of proof onto those who think that moderately elevated thyroid hormones impair sleep. Obviously, there is some point at which levothyroxine or hyperthyroidism is guaranteed to impair sleep.

My TSH (5.25) looks higher (more than double) than it was last time. It's worth noting that a while ago, after the previous test but before this one, I had taken some high doses of iodine. This is sufficient to explain the rise. The acute suppression of thyroid function, and corresponding increase in TSH, by high dose iodine is well documented. Long term iodine, if memory serves, has no significant impact. I don't know the impact of cessation.

Symptom notes:
I arguably qualify for restlessness. However, I certainly do not qualify for increased appetite. I have trouble with appetite. My appetite is very low, to the point where I have some interest in drugs for anorexia (e.g. cyproheptadine) in low doses. For other symptoms listed, I experience them in a mishmash fashion, some of which may or may not be clinically significant.

It's also worth noting that palpitations are extremely rare for me. I can't remember the last time it occurred (probably months ago). I'm generally unaware of my heart. This is especially true during tachycardia. Tachycardia usually reduces my awareness of my heart quite significantly. I assume that this is, at least in part, because of the reduced preload as the heart beats faster. The main times that I can feel my heart are when I'm very relaxed and can feel a slow but firm pulse.

It isn't easy to find objective references of hypothyroidism causing heart palitations, but several anecdotes on reddit came up (like this one and this one).

Other notes:
During my thyroid research awhile ago, I came across this post on discussing thyroid hormone resistance as a possible explanation for CFS. I generally trust people on lesswrong to be meticulous and unbiased. They are hardcore rationalists whom take accuracy very seriously. You'll note that in the very last paragraph, for the five preEdit: for memises differentiating hypothyroidism from CFS, the author, like myself, rejects lowered heart rate in hypothyroidism (premise #4). Therefore, effective hypothyroidism would remain a valid diagnosis in my case.

Personally, unless I'm missing something, I don't see any value in diagnosing Graves. Thyroid status strikes me as the only relevant factor. More precisely; effective thyroid status. Also, it appears that I fall within reference range for all these values. Nevertheless, I'm willing to take the test if there is a specific reason or if we just need to get it out of the way.

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 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.
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.
The same was found for non-insulin-dependent diabetes. Butter increased insulin spike, but olive oil did not.

Likewise, a meta analysis of randomized controlled trials found that replacing animal protein with plant protein improved glycemic control in diabetics.

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 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.

(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.

(3) Moldofsky, H., & Scarisbrick, P. (1976). Induction of neurasthenic musculoskeletal pain syndrome by selective sleep stage deprivation. Psychosomatic medicine, 38(1), 35-44.

(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.

(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.

(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.

(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.

(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.

(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.

(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. (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.

(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. (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.

(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. (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.

(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.

(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.