This is just as I expected, though I'd also be unsupervised by opposite findings. I'm yet to find why symptoms such as insomnia are so often cited for hyperthyroidism. I see a few possibilities. One is that it's very slow onset effect that takes more than 2 months to develop (personally, this seems unlikely). Another is that it only effects people with preexisting anxiety or hyper-arousal (strikes me as a likely partial explanation). A third is that it only effects people with the most extreme hyperthyroidism (also strikes me as partial explanation). Finally, it's possible that the entire thing is a myth. Authors of another study from 2011 noted that "[sleep] is being characterized as poor without further elaboration." I think it may be the case that people are just assuming patient's sleep issues are caused thyrotoxicosis because it seems like it would, when in fact only a small fraction actually are. Perhaps thyrotoxicosis even turns depressive insomnia into anxious insomnia, thereby confusing physicians.

The next question is whether treating light to moderate hyperthyroidism would resolve insomnia. This would answer some of the above possibilities. However, I'm uninterested in severe hyperthyroidism because it is above the maximum treatment dose I commonly see, namely 500 mcg thyroxine.

25.2 out of 33 is quite high (i.e. very positive results). In fact, those results seem too good to be true, and are likely due to the limitations of the study. In particular, by 54 months of treatment the non-responders or those with side effects would have already stopped taking thyroxine. Nonetheless, the data is consistent with other studies indicating that supraphysiological doses of levothyroxine has few and mild side effects (regardless of the sample population).

This makes RLS sound very similar to Parkinson's.

Note that melatonin peak values were altered by thyroid function. Namely, peak melatonin was inversely correlated with thyroid activity (inversely with T3, positively with TSH). This leaves open the possibility that thyroid activity imposes a circadian pressure that is counteracted by lifestyle choices. Constant lighting studies would be required to properly test this.

This is plausibly partly responsible for carbamazepine being effective for epilepsy.

Thyroxine working in about 50% of patients was also found in Bauer et al. This dose was not quite as high as Bauer, but 235 mcg is still above a full replacement dose.

I'd like to see results on minor depression. However, such studies are unlikely.

This is the highest dose of levothyroxine that I've seen administered. Even treatment for thyroid cancer rarely goes beyond 300 mcg (or even 200 mcg, which is more common).

I'm not sure what they mean here by 'weekly basis' Levels did change on a weekly basis. Hourly, on the other hand, they did not change.

I'm surprised that TSH didn't drop a few hours after liothyronine administration. I see two possible reasons; either TSH is a measure of average thyroid activity, or T3 has slow/delayed effects. If the latter is the case, then there doesn't seem to be any reason to spread out liothyronine doses.

Looks like preference for T3 increased as the number of hyperthyroid symptoms increased. It would be interesting to know if those are the same patients.

Will need to check up on that. I recall T4 being less potent.

It appears that even mild thyroid elevation radically cuts TSH. Makes sense.

Graves disease has a average free T3 at least 3 times the upper normal range. This implies that there is only a little bit of wiggle room between high thyroid status and thyrotoxicosis. However, free T4 is at about twice as high as upper normal, so the total thyroid activity may be closer to 3.5 or 4 times the upper normal (assuming that T4 is roughly 10 times less potent than T3)

Most thyroiditis patients had total T3 in the upper reference range. Free T4, on the other hand, was nearly all above reference range. Graves' disease had half somewhat elevated and half extremely elevated levels for bot total T3 and free T4. I now just need data on free T3 (which in my recollection would be expected to scale tightly with total T3, so I may be able to predict the values).

Note that the high dose was because they were increasing the dose based on symptoms. That is to say, as the thyroid gland produced less thyroid hormone, they increased liothyronine dose to compensate.

If this holds true, I'd expect rapid blood volume expansion from thyroid hormone. I'm also interested in whether thyroid hormone stimulates the production of albumin, given its anabolic properties.

300 mcg is on the high side. Nevertheless, lack of hyperthyroid symptoms is not surprising. The highest dose administered in the Skinner study was 275 mcg, but that was merely for the elimination of hypothyroid symptoms.

It seems like doses would need to be quite high in order to become symptomatic. The only counterevidence I'm aware of so far is anecdotes I've read online. Thus, it appears that high doses are well tolerated.

If the mechanism is really the same as alpha blockers, then the blood volume expansion may be expected to be similar in constitution. However, I would expect more red blood cells in thyroid mediated volume expansion compared to alpha blockers. The reason, obviously, is because of the increased oxygen demand from thyroid hormone.

This is consistent with my previous assertion that T3 may result in greater energy expenditure than T4.

Thus, a 15% expected increase would be reasonable for a euthyroid subject such as myself. However, since T3 reduces weight compared to T4, it is possible the weight loss indicates greater energy expenditure.

Interesting that the diet group worked better. I'd like to see if it's statistically significantly better than the drug group. It's also worth asking whether sodium was the only important dietary change, or if avoiding sodium caused many other dietary improvements.

Fascinating. Neck circumference suggests that sodium intake may indeed be the significant dietary factor. The recommended diet wasn't even very restricted in sodium.

Is there anything it can't do? I have noted, however, that larger doses cause nausea for me. That is, 3 or more grams on an empty stomach. I just vomited after taking 7.5 grams before my meal, but I have not yet established the causal link. It is the largest amount I've ever taken at one time. I suspect that it may have contributed significantly, but that it was also one out of half a dozen factors.

This implies that T4 and T3 are not identical, but I want to check the study further to see if half-life comes into play. The T3 group could theoretically have higher daily thyroidergic exposure, but maintain TSH because they experience a daily dip. Multiple dosing at least partly solves this issue. Controlled release tablets would be ideal.

So, given that thyroid hormone resistance does exist, the remaining question is whether it is common enough to explain some cases of CFS or similar conditions. Unfortunately this paper is not in english, but the abstract provides enough information to google more.

I ought read the full study to see the proposed mechanism. The vasopressin effect is not surprising at all, but the oxytocin effect was unexpected for me. That may be because I know more about vasopressin than I do oxytocin.

This is the only group with a TSH significantly below the reference range. The reason, of course, is that the patients with the most symptoms ended up getting the highest doses of thyroxine (T4) by the end of the study.

The study does not provide enough information to determine whether this is meaningful. It appears to be meaningless. If they had used a crossover design, then this might be useful.

Note that they did not have a mild hyperthyroidism group, whereas they did have a mild hypothyroidism group.

Before reading the study, I'll state that my suspected mechanism is dry skin. Hyperthyroidism causes oily skin, while hypothyroidism causes dry skin. Thus, I'd expect hypothyroidism to have similar symptoms to using harsh detergents/soap and/or scrubbing too frequently or too hard.

This seems like an obsurdly obvious prediction to me. Is also lends credence to the idea of positive feedback loops in sleep disorders, particularly insomnia. That is to say, sleep insufficiency can be expected to increase arousal rather than increase sleepiness. This is also supported by the data that sleep deprivation increases evening cortisol the following evening.

It would be interesting to see if this metric applies to healthy subjects.

This is an amazing review for practical purposes. Here's to applicable science!

No control group? Being awake for 27 hours will do that. They need to use either no light and/or sleeping subjects as controls..So far I've only read the abstract, so it's possible that they address this further down.

If talking a single generation, this would be the number to use. That is, the 55 segment scrambling that your parents got will be passed on to you.

I was talking with someone about having different ancestry from one's siblings. I was unsure of how frequently chromosomal gene swapping occurs. This answers the important question, which is units of inheritance. That is, instead of calculating inheritance as 23 units, slightly less than 100 appears more accurate. This makes percentage DNA almost precisely the expected value, but the standard deviation should be such that rare cases of one sibling being e.g. Jewish while the other sibling lacking that ancestry may occur.

This does suggest some of the supposed heritability is actually prenatal environment (or some other analogous factor). It's also possible that e.g. mitochondrial DNA plays a bigger role than previously recognized, much how thyroid status is the #1 predictor of mental retardation. Perhaps IVF will shed further light on the issue.

I'm looking for the smallest standard deviation in an adopted sample to compare the average difference to that of identical twins. This study suggests that the SD in adoption is identical to the SD in the general population. This supports the idea that lower SD in adopted identical twins is entirely down to genes (or, in principal, prenatal environment).

Note that this comment is referring to this Reddit inquiry.

That sounds incredibly high to me. 3000 mg is the absolute maximum intake that could ever be considered 'low' sodium. Under 1500 is usually considered ideal. Would, then, a diet aiming for half the sodium be twice as effective?

Sounds like 500-1200 mg per day (i.e. 125-300 mg four times daily). While 500 mg daily seems fairly normal, 1200 mg is rather high. That dose may require highly bioavailable forms to avoid side effects. I think that this is the study I've been searching for ever since I lost track of it. So far, this is the highest dose of elemental magnesium that I'm aware of being studied.

This is exactly what I expected to find. This is why I doubt that there is significant risk to high dose T3 taken in the morning. In fact, given that hypothyroidism is also associated with increased fracture, I'm inclined to think that thyroid hormones per se play no role whatsoever, but rather the downstream effects. That is to say, hyperthyroidism disturbs sleep, thus harming bones. I conclude, then, that so long as sleep quality is maintained, hyperthyroidism is plausibly safe for the bones.

(see 45 seconds into video)

This could be very handy for lowering the pH of the gut (increasing the acidity). As explained in other Greger videos, an acidic gut is desirable because good gut bacteria produce acids and thus are the bacteria that thrive in an acidic environment.

Currently, I'm taking magnesium citrate. My concern is that the unabsorbed magnesium is alkalinizing my gut. Vitamic C should be able to counteract this (assuming it is indeed an issue). That does make the assumption, however, that the hydrogen ion makes it to the large intestine. That is to say, that the ascorbate does not become a conjugate base.

Precisely what I'd expect. However, I was hoping to find a placebo controlled trial. I'm nearly certain that magnesium will show benefit. I'm less confident that such studies will use adequate doses of magnesium for the effects to reach statistical significance.

There are two additional types of meals that will be needed to clarify this issue. That is, one with a high-fat high-fiber meal, and another with a low-fiber high-carbohydrate meal. Nonetheless, one could argue that, in practice, carbohydrates correlate with fiber.

In other words, it was isocaloric between the two groups, in that similar subjects were fed similar calories.

Doesn't offer naltrexone.

Liothyronine does not raise blood pressure despite the rise in heart rate. The reason that respiratory rate (RR) was not changed may be because the increased cardiac output compensates for the increased oxygen demand.

This doesn't sound like adequate protein to stimulate bile. Therefore, this study does not elucidate whether fat is necessary for lipid soluble nutrient absorption. Nevertheless, it does show that fat is sufficient.

This is some of the better evidence that fat is not necessary for lipid bioavailability. I'm trying to find out if bile alone is sufficient.

They also gave 10 biscuits (full text). This could potentially destroy the entire premise of the study. They estimate that the entire meal contained between 6 and 20 grams of fat, depending on which milk was given. Skimmed milk contains 0.2% fat, so 430ml provides less than a gram. Therefore, the skimmed milk group obtained most fat from the biscuits. Six grams is certainly enough to substantially enable bioavailability.

I'd like to see a trial of hemp protein for chronic fatigue syndrome.

This is good for my purposes. It means high doses can be taken for brain effects without disturbing stomach acidity. The question remains, of course, whether coinciding CNS tolerance develops.

H1 antihistamines enhance the opioid high in humans. Hospitals sometimes administer antihistamines in combination with opioids. It's not hard to find people online who are using this combination recreationally.

Cool. That's about 480 Fahrenheit, which is over a hundred degrees more than I roast my flax (350F). However, they only roasted for three and a half minutes (from full text), compared to the 10 minutes that I use. Nevertheless, heat sensitive degradation tends to be logarithmic, so I'd likely still be fine if I cooked it for an hour (at least for lignans. The omega-3 would probably oxidize, though)

At first glance I thought that this study was useful, but I'll need to examine the time frame more closely. Six months after initial use may not be enough time for cancer to develop, so to be useful it should be 6 months of use years ago. I'll have to look at smoking studies to get a better sense of how to interperet the data.

Presumably this captures the "gravity" effects of low dose salvia. This is the metric that interests me most.

The T3 half-life, therefore, is only 14.25 hours (14 hours and 15 minutes). I calculated this based on taking the peak value and comparing it to the baseline value 22 hours later.

Since they've been on the same dose during this study period, the baseline value is what's left from yesterday's peak, and can be assumed to be tomorrows trough. Since the drug took 2 hours to peak, there are 22 hours remaining to reach trough/baseline values.

In other words, clonidine elevates CO2. I'm not yet sure whether this is a good thing.

Based on water intake of 10ml per 100g body mass, that should translate to 0.5 mg/kg. This is one of the few studies using LDN as opposed to ULDN.

The question remains, then, for the general population with SA.

I suspect it also plays a role in UARS. This study probably selected people with heart failure because the fluid retention leads to a more dramatic response. Hypertension was likely a neccesary ethical consideration. Hypotension is common in UARS; therefore, one is unlikely to find a study administering diuretics to UARS patients. That leaves correlation as the only tool available to confirm this suspicion.

That is rather unfortunate. It appears rather dificult to have in impact on albumin metabolism.

The question, then, is whether the opioid receptors are involved at all in this upregulation. For example, it could be mediated by TLR4 or filamin A.

A sound argument. This possibly could increase the antidepressant action as well.

2 mg appears most effective. download PDF here.

I would not expect doses this small to impact the opioid receptors.

Symptoms in the treatment group continually improved, whereas symptoms in the placebo group plateaued. Thus, I'm interested in seeing a longer treatment period. Projecting from symptom scores, elimination of symptoms would occur in about 10 days.

I find the increased nighttime blood pressure suprising. Increased heart rate, on the other hand, is exactly what I might expect. Given that it is diastolic pressure that is elevated, I take it that the increased heart rate is the cause. If not, it could be that a stressor, like a hypopnea, is the underlying cause.

Interesting. Conventional doses of naltrexone appear effective for sleep apnea. I'll be interested in seeing if LDN fairs well.

I've found elsewhere that mu agonism combined with delta antagonism provides analgesia while minimizing tolerance.

This further supports the link to ME/CFS. The ratio in the referenced study is about 2.5 to 1: female to male.

This makes Upper Airway Resistance Syndrome a prime suspect for ME/CFS. I presents many of the same symptoms, and may be the instigating factor. That does not mean, however, that UARS is the only cause, nor that treating UARS is necessarily sufficient to treat ME/CFS; a feedback loop may mean that other factors must be attended to.

Nimodipine reduced morphine dose in already tolerant patients.

The entire article is begging the question. Is there strong evolutionary pressure in favor of intelligence? Is stupidity, like shortness, adaptive? Modern data shows that intelligence impedes reproductive success. Therefore, there is a strong burden of proof on those suggesting that intelligence was ancestrally adaptive.

The full text describes how ultra-low-dose naloxone and naltrexone enhance opioids at very slim dose margins. A mere two fold difference on naltrexone dose can determine efficacy: 2 micrograms is effective whereas 4 is not. What's more, this optimal dose changes with sex, mouse strain, opioid agonist used, etc.; this making precise dosing challenging. The mechanism suggested is that filamin A has two binding sites, where only 1 has the desired effect.

This sentence appears to indicate equal potency between the two drugs.

So, naloxone has a 200 times higher potency at Filamin A compared to opioid receptors, but I need clarification on whether naltrexone achieves similar potency.

Niacin does not appear to elevate IGF-1.

That's surprising, but it does not necessarily mean that the mechanism is not the lowering of FFAs. Clonidine does lower FFAs, but individual responses to FFA reduction may vary in magnitude.

It's possible that this is related to the hyper-vigilance observed in depressives.

I'll have to look at this meta-analysis more closely, but they are likely looking at total sleep deprivation for one night, or partial sleep deprivation for one or several nights. Partial sleep deprivation tends to deprive more REM sleep via early awaking. I'd expect the greatest effect from SWS deprivation.

Those standard deviations look way too high. Two standard deviations out, people are getting weaker. In other words, it looks like they are using group mean and standard deviation as opposed to individual change before and after. In yet other words, the study is under-powered and useless. It looks like HFT is better.

Full text summary: Beta 1 but not beta 2 is involved in REM sleep generation. High dose propranolol (which is not selective) practically obliterated REM sleep. Selective beta 1 agonism restored REM, while selective beta 2 agonism did not.

No benefit of pain.

Pain = less gain.

Citation needed. The opposite is true in patients with PTSD.

Since the pain is caused be SWS interference, it might be difficult to disentangle cause and effect.

That's an extremely high rate of hypotension in UARS. This may be what I have. If UARS causes hypotension, then sleep apnea (SA) may be different because of its link to obesity.

This doesn't quite clarify the effect of 5HT2C antagonism in the absence of 5HT2A antagonism.

I notice that their study does not support their conclusion in the slightest. Firstly, the study does not actually show that a sleep diary is more accurate than the Pittsburgh Sleep Quality Index (PSQI). Secondly, the PSQI may be picking up sleep quality metrics that are hard to measure. Lastly, what matters is subjective experience, so, franky, F*** them for arbitrarily deciding what is a good sleep measure.

It is interesting to note that they report potentiation of 10mg but not 5mg of morphine. Thus, it is possible that antihistamine potentiation is dependent on dose of opioid, or that antihistamines raise the analgesic ceiling. That is to say, antihistamines may raise the maximum possible effect from opioids without raising the effects of lower doses much. However, antihistamine combination did tend to enhance the effects of lower dose morphine, but the effect was not as dramatic (therefore not reaching statistical significance in a study of this power).

Apparently, clonidine is active at one quarter of the starting dose. Namely, it is active at 25 micrograms (mcg) compared to the 100mcg starting dose.

This is precisely the results I would expect. However, I completely disagree with their interpretation.

People with high blood pressure (BP) can tolerate a reduction in BP without instigating compensatory mechanisms. People with normal or low BP would invoke compensation by the sympathetic nervous system in response to alpha blockade. This would counteract the depressant effects of adrenergic antagonism. Indeed, adrenaline and noradrenaline elevate in response to standing, which I find to be an obvious prediction. Thus, the lack of benefit from prazosin in these subjects may be mediated by an increase in adrenergic receptor activation other than the apha1-adrenoreceptor; in particular, the beta-adrenergic receptors are likely at fault. Propranolol, a beta-blocker, is used for PTSD, so this mechanism seems well substantiated.

The study apparently found benefit for patients with BP over 110 (with more benefit for higher BP). Thus, I would conclude that systolic pressure below 110 induce compensation.

Increased sensitivity to cold by phenoxybenzamine could be the result of heat dissipation via peripheral vasodilation.

Thus, the effective pharmacological half life of phenoxybenzamine is roughly 1 day.

This is rather fast. It means that tolerance and withdrawal should develop relatively rapidly. This is consistent with the "first dose effects" observed with alpha blockers.

This is interesting but not exactly surprising, given that both are depressants. What is surprising, however, is the contrast between this and the fact that stimulants also enhance morphine analgesia.

Potentiation of Opioid Analgesia by Psychostimulant Drugs: A Review00084-0/fulltext)

Post-exercise, diastolic pressure is higher than baseline; compression garments exaggerate this effect

Thus, compression garments may prevent circumstantial hypotension. In this case, one possibility is that the compression is delivering blood to the heart that would otherwise be shunted to the skin for heat dissipation.

These trained athletes have a BP of about 100/60 at rest. This is substantially lower than the roughly 120/80 BP that I've seen elsewhere. This likely limits the drop in BP seen post-exercise.

This is important because it implies that syncope or incomplete syncope as a result of vasodilators may not be dependent on actual blood pressure. It means that it is theoretically possible that vasodilators will acutely increase blood flow despite a drop in BP, depending on the body's level of compensation via increased cardiac output.

Alternatively, it could have been nocturnal hypotension that was causing the sleep disruption.

Surprisingly, beta-blockers, unlike alpha-blockers, appear to impair sleep.

Surprisingly, beta-blockers, unlike alpha-blockers, appear detrimental to sleep. I would speculate that this could be the result of a shift in autonomic tone, similar to how caffeine tends to lower heart rate.

This suggests that a beta 2 agonist may be appropriate for sleep.

Note: they appear to be talking about the number of dreams recalled (due to awakenings) rather than the actual number of dreams.

Presumably, this is just a result of blocking some of the effects of cocaine to begin with.

This is all very interesting. It is also true that, in the treatment of depression, there is a relatively low dropout rate due to side effects from treatment with T3 (liothyronine).

liothyronine (T3) augmentation in the treatment of depression

Interestingly, the superiority of magnesium citrate over other forms is most evident in salivary excretion, both acute and chronic. In particular, I had been led to believe that amino acid chelate was superior. Given that these results are consistent superior plasma levels, I take this to be reasonable evidence that the citrate form is superior for a given value of elemental magnesium. In this case, 300mg elemental Mg.

This is precisely the type of information I was looking for. Wikipedia implied T4 should be taken with long-term T3, but the reasoning was poorly explained. However, I'd like a more official source for this case report.

This case would also express no rT3 (reverse-T3). Thus, it appears that neither T4 nor rT3 serve any vital functions.

Standard LDN is 4.5mg. According to this data, that may be orders of magnitude too high. Nevertheless, LDN has been found effective.

I've not yet found the impact of equol on estrogen alpha and beta. The benefits in epidemiological research suggest it is likely similar to other phytoestrogens; partial antagonist at the alpha receptor and agonist at the beta receptor.

This is likely do to the reduced carbohydrate intake rather than increased fat intake. Since carbohydrates generally insulin sensitivity, it's likely that this additional insulin resistance is acting as a confounder (as well as, presumably, a standard deviation widener). Thus, I would expect similar results during hypocaloric carbohydrate restriction.

In other words, vegans have higher total, but not free/unbound, testosterone.

This potentially explains why tianeptine gives me energy. I've seen several other anecdotal reports as well. However, I've never taken illicit or prescription opioids, so I don't have a proper mode of comparison.

... Or not. It's just as likely, if not more likely, to be biological. Unless there has also been a sex-specific bias in autism diagnosis, it could just as easily be argued that men's autistic personalities cause this effect

Of note, vegans consume more iron. Since non-heme iron absorption is regulated (i.e. titrated in proportion to stores), this does not mean vegans absorb more iron. Importantly, however, it does translate into no greater risk of anemia for vegans as compared to meat eaters.

i.e. 195 ng/dl, or 6.8 nmol/l. This is not extraordinary, as it is roughly the 2.5th percentile of normal testosterone for most ages.

This supports other evidence, such as the fact that vegans, despite their lower cholesterol, have higher total testosterone.