147 Matching Annotations
  1. May 2020
    1. assessed prospectively in men and women smokers before and then day-by-day

      No control group? This study tells me literally nothing. It just demonstrates that the effects of tobacco are not the same as nicotine. That was already obvious.

    1. While somewhat modest in size, the literature on chronic tolerance to nicotine in humans is reasonably consistent in showing clear evidence of tolerance to subjective mood effects but little or no tolerance to cardiovascular, performance or other nicotine effects

      This is what I'd expect for tobacco, but it tells me little about nicotine. Most of the subjective effects are not from tobacco, so It's still plausible that nicotine does not develop tolerance. Indeed, the effects that don't go away are the effects expected from nicotine.

    1. Hippocampal size of nonusers reflects a direct relationship to memory function; the smaller the hippocampus, the poorer the memory function. Individuals who use marijuana and tobacco show an inverse relationship, i.e., the smaller the hippocampus size, the greater memory the function. Furthermore the number of nicotine cigarettes smoked per day in the marijuana and nicotine using group appears to be related to the severity of hippocampal shrinkage. The greater the number of cigarettes smoked per day, the smaller the hippocampal volume and the greater the memory performance. There were no significant associations between hippocampal size and memory performance in individuals who only use tobacco or only use marijuana.

      They mention abstainers below. It appears that they are saying that there is memory improvement compared to complete non-smokers. Will need to check actual study. Note that my interest in nicotine is confounded by the use of tobacco.

      Edit: eyeballing the graphs, it appears that the tobacco group did the best, while the marijuana plus tobacco group did the worst. Given the small sample size and high variability, these are not statistically significant. Nonetheless, that suggests that marijuana never benefits memory. Edit: eyeballing the graphs, it appears the tobacco group did the best, while the marijuana plus tobacco group performed worst. Given the small sample size and high variability, these results are not statistically significant. Nonetheless, it suggests that marijuana is never a benefit to memory.

    1. 16S sequencing showed that nicotine perturbed bacterial diversity and community composition of gut microbiota more pronouncedly in HFD mice.

      Note that nicotine by itself had minimal impact on the microbiome. Nicotine speeds up transit through the intestine. Thus, the reason nicotine plus a high fat diet was detrimental is likely that nicotine is increasing the throughput of harmful prebiotics (e.g. protein in particular). When lots of fiber and resistant starch is present (will need to see if they provide this info for their diets), then nicotine mostly just carries it to the small intestine faster (and possibly reduces fermentation time).

      Given that opioids have a negative effect on the microbiome, I was expecting nicotine to have a positive effect. Perhaps it would have a positive effect were there more resistant starch in the diet.

    1. Results reveal a significant shift in the gut microbiome and metabolome within one day following morphine treatment compared to that observed after placebo. Morphine-induced gut microbial dysbiosis exhibited distinct characteristic signatures, including significant increase in communities associated with pathogenic function, decrease in communities associated with stress tolerance and significant impairment in bile acids and morphine-3-glucuronide/morphine biotransformation in the gut.

      Unsurprisingly, various substances appear to disrupt the microbiome; artificial sweeteners are not unique. Given that I don't worry about opioids, I probably shouldn't worry about sweeteners.

      However, opioids are known for causing constipation. That is to say, they have a clear effect on digestion. Perhaps I should worry about opioids rather than not worry about sweeteners.

  2. Apr 2020
    1. Although it has been proposed that NNS do not affect glycemia (3), data from several recent studies suggest that NNS are not physiologically inert. First, it has been demonstrated that the gastrointestinal tract (4,5) and the pancreas (6,7) can detect sugars through taste receptors and transduction mechanisms that are similar to those indentified in taste cells in the mouth. Second, NNS-induced activation of gut sweet taste receptors in isolated duodenal L cells and pancreatic β-cells triggers the secretion of glucagon-like peptide 1 (GLP-1) (4,5) and insulin (6–9), respectively. Third, data from studies conducted in animal models demonstrate that NNS interact with sweet taste receptors expressed in enteroendocrine cells to increase both active and passive intestinal glucose absorption by upregulating the expression of sodium-dependent glucose transporter isoform 1 (5,10,11) and increasing the translocation of GLUT2 to the apical membrane of intestinal epithelia (12).

      This supports my previous assertion that the effects of artificial sweeteners on the microbiome are taste-mediated. However, I did not predict the intestinal taste receptors. That means that my previous way to falsify the claim, such as delivery by oral gavage, is no longer adequate. Nonetheless, interesting things could be learned from such tests.

    1. These variations were related to inflammation in the host

      In which direction? This statement makes me wonder if inflammation caused the changes in the microbiome.

      It seems possible that the sweetness itself is the ultimate cause. To test this, a study using oral gavage. It's easily plausible that the flavor alerts dietary patterns (I believe humans eat more calories in response to sweeteners, will need to check on source). Alternatively, direct effects on the brain, and downstream effects on the body, is also not out of the question.

      The reason I suspect taste-mediated effects is that it seems unlikely that so many completely unrelated sweeteners would have such similar effects. However, one might might expect more similar results than those found if it were the case (or the dose is so high that the taste changes for some, e.g. saccharin).

    1. In the first of two enzymatic steps that produce high-glucose syrup as an intermediate to high-fructose syrup and other products, bacterial α-amylase is employed at pH 6–7 and about 105°C to hydrolyze starch purified by wet milling to roughly DE (dextrose equivalent) 10, DE being the percent of reducing end-groups in the aqueous sugar mixture relative to those in pure glucose of the same concentration. This indicates that the average maltooligosaccharide produced has a DP (degree of polymerization) of 10, although the mixture has a very wide DP range. DE 30 or more can be attained if the reaction proceeds to completion, but DE 10 is chosen to minimize the probability of pseudo-crystallization at lower DEs and the extent of alkaline-catalyzed isomerization of the reducing-end glucosyl residue at higher DEs.In the second step, at pH 4.3–4.5 and roughly 60°C, fungal glucoamylase and a small amount of pullulanase (pullulan 6-glucanohydrolase, EC 3.2.1.41), the latter used to rapidly hydrolyze the α-1,6 bonds from the original starch feed, convert the maltooligosaccharide mixture to approximately 96% glucose (dry basis). The remainder is composed of byproducts from α-amylase hydrolysis plus mainly isomaltose [α-glucopyranosyl-(1,6)-glucose] and isomaltotriose from the glucoamylase-catalyzed condensation of glucose.

      If I'm understanding this correctly, all I need is alpha amylase (easily obtainable) and beta amylase (AKA glucoamylase, also obtainable). When buying these, I've found that alpha amylase is advertised as simply amylase, whereas beta amylaze is advertised as glucoamylase

      This mentions both pH and temperature, but fails to mention time. I'd expect it only takes a matter of hours (or less).

    1. RESULTS: The rate of discontinuation due to side effects was significantly higher in the control group than for the patients (38% versus 0%). The severity of the side effects in the controls increased significantly during treatment with T(4). The side effect scores of the patients were higher than those of the controls prior to T(4) treatment, but did not change significantly during the treatment period. Although the serum concentrations of thyroid hormones rose significantly in both groups, concentrations of fT(3) and fT(4) were significantly higher in the controls.CONCLUSIONS: Healthy controls and depressed patients respond significantly differently to supraphysiological T(4). Healthy controls experience higher elevations of thyroid hormones in response to supraphysiological T(4), thus inducing significantly more side effects and discontinuation.LIMITATIONS: Open-label study; groups were studied at different times; in contrast to healthy controls, depressed patients were also taking antidepressants.

      Brilliant study. Astonishingly, ~500 mcg thyroxine only increased FT3 about 20% in depressed patients. In controls, it nearly doubled FT3 (about 80# increase), Thyroxine doubled total T4 and total T3 in both depressed and controls. That lines up with the FT3 rise in controls, but is still much lower than I'd expect from this dose.

      Note that the depressed patients had equal thyroid symptoms before taking thyroxine, so experienced no increase. The pre-treatment depressed patients, treated depressed patients, and treated controls all had an equal number of thyroid symptoms. Thus, only the pre-treatment healthy patients lacked hyperthyroid symptoms. This is interesting because the treatment was 500 mcg thyroxine (average 484 mcg), which you'd expect to cause more symptoms.

      This could mean either that the depressed patients had as many symptoms alleviated as they had caused by thyroxine, or that depressed patients simply had lower thyroidergic activity. The latter is supported by the fact that free T3 and free T4 rose 2 or 3 times less in treated depressed patients compared to treated controls (from full text).

      It's also possible that the pre-existence of symptoms masked their appearance (in which case increased severity might be expected). I doubt that this is the case. A few symptoms trended toward improvement.

    1. REE decreased approximately 15% when TSH increased between 0.1 and 10 mU/L.

      The individual change in REE to a given change in dose varied radically. The dose change was only 50 mcg, which seemed to change TSH about half what they've calculated for 15% REE change. That is to say, it looks like a 50 mcg dose reduction will only raise TSH from 1.0 to 5.0, not to 10.0. This is my personal guesstimate, and will need to be properly calculated from other studies. My point is merely that 50 mcg will not cause the full 15% REE increase. Additionally, the response to 50 mcg may depend on initial TSH.

      It looks like TSH changes that remained hyperthyroid (i.e. bellow 1.0) had little effect on REE. This might be because the body is maintaining thyroid status, or that REE is more like an on/off switch. However, this only covers relatively small changes in thyroxine dose.

      It is unclear how supraphysiological doses effect REE. It seems likely that the ten times greater dose (500 mcg) used for depression would significantly increase REE.

    1. Thyroxine treatment significantly lengthened TPX animals' cycles (average increase: 0.28 h) but did not affect intact rats' circadian rhythms.

      This suggests that hypothyroidism shortens the circadian cycle, while hyperthyroidism does nothing. This is disappointing, and also counter to what I expected. However, it could still be consistent with my expectations if these effects are behaviorally mediated. That is to say, it could be greater stimulation that keeps them awake longer (which in turn effects the body clock). If that is the case, the alertness/dullness effects could be countered by depressants/stimulants, which would reveal the direct circadian impact.

      Additionally, I'd like to know if T3 doses at wake time could provide any entrainment (or at night time). The half life of T3 is short enough that reveal phase effects. T4 only demonstrates net effects; like getting light exposure all day long, T4 may both delay and advance circadian phase.

      Also note that all conditions have a distinct rightward tilt when graphed. That is to say, they have a body clock longer than 24 hours. It's quite plausible that the thyroid hormone could interact with zeitgebers.

  3. Mar 2020
    1. The mean percentage removal of stains for test group was significantly higher than control group.

      Note that this was a two week study. It's hard to guess whether greater benefit would occur over longer periods.

    1. The mean time taken in the group II (bromelain) was 335.30 seconds which was nearly equal to the mean time of group I (papain) of 352.33 seconds.

      This is slightly longer than normal teeth brushing sessions, but the frequency of brushing implies that my bromelain/papain toothpaste is more than adequate to deal with dental caries. Additionally, carries prior to tooth extraction are generally going to be small, meaning that a single brushing session might remove them.

    1. l-thyroxine was added in the dose of 100 microm daily for 4 weeks.

      This is the same dosage that another study found to be indiscernible from placebo. I suspect a couple things are at play.

      The first is that these are treatment-resistant patients, meaning that we already know they are not susceptible to placebo; given that we are effectively comparing combination therapy to SSRIs alone, this means that the SSRI only stage is not experiencing placebo, thus making the therapeutic effect visible by comparison (retrospective comparison, given that there is no control group).

      The second is that this is combination therapy. It seems likely that thyroxine is more effective when combined with SSRIs.

      Note that this study uses much lower doses than similar studies I've seen, yet had similar results in terms of efficacy rate (roughly 50% responders). I'm not currently certain how the magnitude of effects compares with those studies. Namely, comparing with Pfeiffer et al (350 mcg), Rudas et al (235 mcg) and Bauer et al (482 mcg), and also Bauer et al from 2016 (300 mcg)

    1. The addition of supraphysiologic doses of L-T4 (300 mcg per day) to an otherwise stable medication regimen of standard treatments resulted in a significant decline in depression scores during the 6-week, double-blind treatment phase. At endpoint (week 6), the mean HamD score showed a group difference of 3.7 points in favor of L-T4. Such difference is generally considered to be clinically meaningful in a short-term treatment trial for major depression. NICE used a 3.0-point difference in HamD change scores as a criterion of clinical significance.27

      This is consistent with the open label data. The dose is also similar. Combining this placebo-controlled trial with the three open-label supraphysiological thyroxine studies that I've seen, that is sufficient for me to conclude efficacy. Namely, combining with Pfeiffer et al (350 mcg), Rudas et al (235 mcg) and Bauer et al (482 mcg)

      I would like to see if this study mentions nonresponders. Those three other studies found roughly a 50% response rate. Thus, the effect size in responders may be twice as significant.

    1. CONCLUSION: A 1.5- and 1.3-μg/kg dosage calculation based on actual weight is currently the best estimation for levothyroxine replacement therapy after thyroidectomy.

      1.5 mcg/kg comes to 102 mcg per 150 pounds. That's lower than I'd expected.

    1. L-thyroxine at an average dose of 350 micro g/die. Outcomes were moderate in 39.3% and very good in 21.5%, corresponding to 21-item HAMD scores of < or =16 and < or =8 and clinical judgement. Of all patients, 39.3% had to stop treatment due to nonresponse or side effects.

      This is another study consistent with the 50% remission figure. The dose is also similar: between 235 mcg (Rudas et al) and 482 mcg (Bauer et al).

    1. "As a result, a series of experiments was planned whereby dogs were made edematous or potentially edematous by reducing their blood serum proteins. Various salts were added to their diets and the most striking of these experiments were those in which sodium and potassium chloride were given.2 When sodium chloride was added to the diet of such potentially or slightly edematous animals, fluid storage was prompt and often marked (as much as 40 per cent of the animal's weight in five days) and continued as long as sodium chloride was given. If sodium chloride was omitted, the edema would very gradually wear away. If, however, potas¬ sium chloride was substituted for the sodium chloride in equal amounts at any period during fluid storage, a prompt and marked diuresis occurred."

    1. Fig. 2.

      These make good reference figures. Given that normal T3 values are around 100 ng/dL, Graves' patients had 2 to 7 times normal levels. This is good because it means the symptoms associated with hyperthyroidism may be only on the upper end. Supraphysiological therapeutic doses of T4 (500 mcg) are only 3 or so times the full replacement dose.

      T3 values in painless thyroiditis were only 1 to 3 times normal, except for 1 outlier. Thus, I would predict few symptoms in painless thyroiditis.Or, perhaps, symptoms only in few patients.

  4. Feb 2020
    1. Figure 1c. Temperature before and after T3 administration (T3 given at time 0 hours)

      It appears that the liothyronine could have advanced the phase of circadian temperature. However, since the study had no controls, it is impossible to confirm this hypothesis.

    2. Half-life22.04 hours

      It appears they are calculating based on total T3 rather than added T3. Assuming that the conversion of T4 to T3 remains constant, the half life of the liothyronine dose towards baseline is less than 10 hours (I'd estimate 5-7 hours). Given that this is short compared to other studies, it is likely that the conversion was slowed by the high thyroid status.

    1. At the end of the study neither group was able to identify accurately which treatment period was thyroxine or placebo (table ​(table4).4).

      Fascinating. At 100 mcg, I'd expect one to be able to tell the difference. This is especially surprising given the two groups. Namely, the symptomatic group and the healthy control group. I'd expect at least one group to be able to tell the difference. However, it's worth noting that the TSH between the two groups were virtually identical. The groups were selected based on hypothyroid symptoms rather than actual thyroid status.

      The fact that healthy controls could not tell the difference is odd. It is both not what I expected and cuts against what the related lesswrong article says about discernibility to healthy subjects (odd given that lesswrong mentions this specific study). What may be happening is that the question was not specific enough. If subjects interpreted reduced vitality as a sign that they were not receiving thyroxine, then many might get is wrong. I wish they has a more thorough questionnaire on perception of drug effects. Even an informal "describe the experience" question would be nice.

      All in all, I find it unlikely that this is accurate. There are at least two possibilities. It could indicate that the dose was not high enough, in which case the study is not testing what it thinks it's testing. That is supported the the fact that the TSH of the thyroxine group is barely out of the normal range. The other option, as mentioned above, is that they are not asking the right questions. If that is the case, that also seems to invalidate the findings.

      In conclusion, this result means that we can't trust the study. I'm certain higher doses would be discernable from placebo to subjects. It is likely that it was discernible at this dose (100 mcg) if the right questions were asked. I'm thankful they included this outcome.

      P.S. I found this study completely by accident, then found out it was related to that lesswrong article that I've always appreciated.

    2. Healthy participants had significantly lower scores for vitality when taking thyroxine compared to placebo

      This is very interesting to note. This is some of the most direct evidence that hyperthyroidism shares some symptoms with hypothyroidism. I'd still like to know if liothyronine (T3) would show the same results. I suspect T3 would be better, especially given that it may be less likely to disturb sleep (because of the half life).

    1. Surprisingly, treatment with supraphysiological doses of L-T4 did not cause significant effects on sleep architecture. However, the increase in body movements and REM density was close to reaching statistical significance.

      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.

    1. At the time of assessment, patients had been treated with supraphysiological T4 (mean dose 368 microg/d) for a mean of 54 months. The total subjective response score was +25.2.

      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).

    1. IN CONCLUSION: in patients with hypo- and hyperthyroidism the circadian rhythm of melatonin secretion is not altered.

      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.

    1. In 12 healthy subjects given 400 mg carbamazepine daily for a period of 5 days, improved sleep continuity and increased slow-wave sleep occurred with treatment

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

  5. Jan 2020
    1. RESULTS: Two patients dropped out of the study owing to side effects. The remaining 7 patients received a final mean dose of T4 of 235 +/- 58 micrograms/day (range: 150-300 micrograms/day). Their scores on the Hamilton Depression Rating Scale had fallen from a mean of 21.1 +/- 4.1 before inclusion in the study to a mean of 8.0 +/- 2.8 at the end of the 8th week. Five patients were full responders, 1 a partial responder, and 1 a nonresponder.CONCLUSIONS: Augmentation with high-dose T4 proved to have an antidepressant effect in more than 50% of the previously treatment-resistant patients with chronic depression and/or dysthymia.

      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.

    1. Thyroxine was added to their antidepressant medication, and the doses were increased to a mean of 482 ± 72 μg/day.

      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).

    1. The present study shows that daily administration of T3 was associated with peaks and troughs in T3 concentration. However, TSH and fT4 remained steady on both a weekly and hourly basis.

      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.

    2. (A)–(C) Changes in markers of thyroid status over the course of the study (mean ± standard error). (D) Changes in treatment preference.

      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.

  6. www.drugwiki.net www.drugwiki.net
    1. L-T3 has proven to be 4-5 times more biologically active and to take effect more quickly than L-thyroxine (L-T4).

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

    1. 0.01 (0.006–0.028)

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

    2. 15.72 ± 10.1

      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)

    1. Fig. 2

      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).

    1. In an observational study of 14 patients, no subjects developed any cardiac or skeletal disease after receiving doses from 25- to 150mcg over a two-year period.41

      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.

    1. RESULTS: In the hypothyroid state, the plasma volume measured by dilution of 125I-albumin (APV) was higher than the calculated plasma volume (CPV) from packed red cell mass, suggesting an extravascular escape of albumin. After substitutive therapy, the CPV showed a statistical increase (P < 0.05), whereas APV remained unchanged. Both ERPF and GFR increased after thyroxine therapy (p < 0.05). In the subclinical group, blood volumes and renal function were similar to those found in the other group of patients when in the euthyroid state.

      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.

    1. Because it is desirable to suppress TSH to less than normal levels in patients with TSH-dependent thyroid neoplasms, and because many patients tolerate 0.3 mg/day of levothyroxine sodium without clinical evidence of hyperthyroidism, it seems prudent to treat patients with thyroid cancer with higher replacement doses of thyroid hormone than is necessary for the treatment of hypothyroidism.3

      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.

    1. Thyrotoxicosis creates a hyperdynamic circulatory state because of a marked fall in peripheral vascular resistance and associated increase in venous return, increased total blood volume, increased cardiac contractility and heart rate.

      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.

    1. Following this observation, the same group conducted a cross-sectional analysis to assess the association among 140 patients with EE and TH replacement hypothyroid treated with LT4. In this study population, REE did not differ significantly between patients achieving low-normal (TSH ≤ 2.5 μIU/mL) vs high normal TSH (TSH >2.5 μIU/mL). Conversely, free T3 level showed a direct correlation with EE, but also with indices of adiposity including body mass index (BMI), body composition, and fat free mass [49]. This latter observation is consistent with other cross-sectional studies that have clearly defined the positive association between circulating levels of T3 and adiposity [50, 51].

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

    2. The authors demonstrated an inverse correlation between TSH and REE with a change of 15% for a TSH ranging from 0.1 to 10 μIU/mL. Of interest, free T4 remained within the normal range in all of the study volunteers. Nonetheless, the changes in REE with different LT4 doses were demonstrated in every patient [46].

      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.

    1. 22.3 per cent (−10.7; 95% CI, −15.6 to −5.7) in the diet group

      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.

    2. Sleepiness and neck circumference were significantly reduced only in the diet group (p = .007 and p < .001 for the time × group interactions, respectively).

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

    1. CONCLUSION: This randomized double-blind, placebo-controlled clinical trial demonstrated that Amla could reduce frequencies of heartburn and regurgitation and improve heartburn and regurgitation severity in patients with NERD.

      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.

    1. The substitution of l-T3 for l-T4 at equivalent doses (relative to the pituitary) reduced body weight and resulted in greater thyroid hormone action on the lipid metabolism, without detected differences in cardiovascular function or insulin sensitivity.

      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.

    1. In almost all cases the genetic basis of RTH lies in mutation of the carboxyl-terminus of the ß-thyroid hormone receptor. RTH is a dominant disorder, except in one family; most individuals are heterozygous for the mutant allele.

      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.

    1. altered thyroid gland function affects vasopressin and oxytocin release from the hypothalamo-neurohypophysial system in the state of equilibrated water metabolism

      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.

    1. 0.19

      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.

    1. At the final study visit, subjects were asked whether they thought their L-T4 doses at the end of the study were higher, lower, or unchanged from the start of the study and which of the two doses they preferred. Subjects were not able to accurately ascertain changes in L-T4 doses (P = 0.54)

      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.

    2. targeting one of three TSH ranges (0.34 to 2.50, 2.51 to 5.60, or 5.61 to 12.0 mU/L)

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

    1. The urticaria resolved upon treatment of the AITD. We also summarize the currently postulated pathophysiological links between the two diseases.

      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.

    1. This review evidence that adults with obstructive sleep apnea may demonstrate diminished vagal tone and higher sympathetic responsiveness.

      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.

    1. In our study, we proved ASV was superior to CPAP in yielding not only greater reductions in RERAs/RDI, but also in yielding significantly greater time spent with normalized breathing—a new metric we devised to highlight the value of looking at airflow improvement as opposed to residual breathing events [4]

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

    1. Ultimately, knowledge on how light affects sleep and wakefulness can improve light settings at home and at the workplace to improve health and well-being and optimize treatments of chronobiological disorders.

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

    1. In contrast, both blue and red lights affected cortisol levels

      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.

  7. Dec 2019
    1. But that number is already known to be about 55 segments

      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.

    2. Whether the input number of segments is initialized as higher or lower, the number of segments tends to converge around 97.5

      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.

    1. Th ough cautions are oft en expressed [e.g., Plomin, DeFries, McClearn, & Rutter, 1997], the fact that reported biological mothers-adopted children correlations are higher than adoptive mothers-adopted children correlations has had a big impact in psychology and on theories of development. Most usually, the correlations have been computed into heritability

      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.

    1. The average IQs of adopted children in lower and higher socioeconomic status (SES) families were 85 (SD = 17) and 98 (SD = 14.6), respectively, at adolescence (mean age = 13.5 years)

      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.

    1. The sodium-restricted diet group received a regimen aiming a maximum intake of 3 g of sodium per day (equivalent to 7.5 g of sodium chloride).

      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?

    1. Case histories are presented showing rapid recovery (less than 7 days) from major depression using 125-300 mg of magnesium (as glycinate and taurinate) with each meal and at bedtime. Magnesium was found usually effective for treatment of depression in general use.

      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.

    1. RESULTS: We observed that poor sleep quality was correlated to low total BMD and legs BMD in middle-aged women after adjusting for potential confounders. Furthermore, when we reran the regression models based on menopausal status in middle-aged women, significant associations between BMD and sleep quality were observed in premenopausal and early postmenopausal groups.

      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.

    1. But, if you take a supplement containing 1,250 milligrams, your body seems to realize that’s too much—and so, clamps down on absorption at the intestinal lining level, and you end up absorbing less than half.

      (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.

    1. Magnesium reduces the intensity of addiction to opiates and psychostimulants (cocaine, amphetamine, nicotine, and others). It also decreases the auto-administration of cocaine and the relapse into cocaine and amphetamine intake, as well as reducing the experimental addiction to morphine, cocaine and other substances in animals. In heroin addicts, alcohol consumers and other drug abusers, the plasma and intracellular magnesium concentration is lower compared to healthy subjects.

      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.

  8. Nov 2019
    1. fiber

      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.

    2. between 535 and 900 kcal, depending on age, sex, weight, and height (16).

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

  9. May 2019
  10. Mar 2019
    1. SBP, DBP, RR, and weight did not change following T3 administration

      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.

    1. Each test salad contained 48 g spinach (Spinach; Dole Food Company), 48 g romaine (Hearts of Romaine; Fresh Express), 66 g shredded carrots (Shredded Carrots; Dole Food Company), and 85 g cherry tomatoes

      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.

    1. The amount of dietary fat consumed with the hot meal (3 or 36 g) did not affect the increases in plasma concentrations of vitamin E (20% increase with the low-fat spread and 23% increase with the high-fat spread) or alpha- and beta-carotene (315% and 139% with the low-fat spread and 226% and 108% with the high-fat spread).

      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.

    1. A single-dose bioavailability study was performed using three commercially available milks (unfortified whole milk and whole and skimmed milk fortified with vitamins A and E).

      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.

    1. CONCLUSION: HSP could have the ability of antifatigue and improve the immunomodulation effect in mice.

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

    1. CONCLUSION: Tolerance to famotidine occurs during continuous administration for 14 days, as previously shown in ranitidine studies.

      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.

    1. We have previously shown that antinociceptive effects of morphine are enhanced in histamine H1 receptor gene knockout mice.

      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.

    1. Especially at 250°C, lignans were degraded rapidly in sesame seeds and rye but not in flax seeds.

      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)

    1. The median exposure to coal tar ointments was 6 months

      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.

    1. The peak T3 concentration after LT3 administration during week 6 was 292.8 ± 152.3 ng/dL, rising from a baseline value of 96.1 ± 7.6 ng/dL

      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.

  11. Jan 2019
    1. Clonidine is associated with diminished susceptibility to hypocapnic central apnoea without significant effect on ventilation or upper airway mechanics.

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

    1. naltrexone in their drinking water (5 mg/L)

      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.

    1. ConclusionsThese findings suggest that in patients with HF, sodium intake plays a role in the pathogenesis of SA.

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

    1. CONCLUSIONS: These findings suggest that pharyngeal edema contributes to sleep-disordered breathing in obese patients with severe OSA, hypertension, and diastolic heart failure. Upper airway edema may contribute to the frequent occurrence of OSA in patients with heart disease.

      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.

    1. Given parenterally in dosages sufficient to produce clear-cut increases in the metabolic balances, neither norethandrolone nor nandrolone produced any significant effects on independently measured synthesis or degradation of albumin.

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

    1. inverse agonist activity was not required for mu-opioid receptor up-regulation and supersensitivity.

      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.

    1. studies after administration during the day. Full daily doses of both drugs should be prescribed in nocturnal dosing regimens, and not in divided doses over the day, for avoiding excessive sedation and performance impairment.

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

    1. Table 1. Analgesic potency of nalorphine compared with morphine for postoperative pain*

      2 mg appears most effective. download PDF here.

    Tags

    Annotators

    1. . Ultra-low doses of opioid antagonists (naloxone and naltrexone), which selectively inhibit the excitatory effects

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

    1. Treatment effects were more pronounced at discharge

      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.

    1. RESULTS: At night (sleep), HR, mean arterial blood pressure and diastolic blood pressure were significantly higher in CFS patients as compared with controls (p < 0.01). During daytime, HR was significantly higher among CFS patients (p < 0.05), whereas blood pressures were equal among the two groups.

      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.

    1. 50 mg naltrexone at bed-time.

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

    1. Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2

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

  12. Nov 2018
    1. The proportion of women with UARS is also significantly higher than for OSAS

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

    2. The most frequent symptoms are excessive daytime sleepiness, fatigue and sleep fragmentation. However, UARS patients also present significantly more often with sleep-onset and sleep-maintenance insomnia, postural hypotension, headaches, gastroesophageal reflux, irritable bowel syndrome, anxiety and alpha-delta sleep

      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.

    1. Nimodipine controlled the escalation of the morphine dose in 9 patients (65%), and placebo in 4 (28%), the difference being statistically significant (P=0.03). The dose of morphine was reduced from 313±52 to 174±33 mg/day (P<0.001) in the nimodipine group, and from 254±26 to 218±19 mg/day (not significant) in the placebo group.

      Nimodipine reduced morphine dose in already tolerant patients.

    1. 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.

    1. 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.

    1. We measure the binding affinity of NLX or naltrexone to FLNA in cell membranes as 4 picomolar, i.e. approximately 200-fold higher than their binding affinity for MOR

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

    2. Naloxone binding to A7 cells was displaced by naltrexone but not by morphine, indicating a target distinct from opioid receptors and perhaps unique to naloxone and its analogs.

      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.

    1. The nutritional supplement ingestion for 3 weeks was found to increase serum GH levels with 70% relatively to placebo, whereas circulating IGF-I levels did not change.

      Niacin does not appear to elevate IGF-1.

    1. HGH response to clonidine was not correlated with plasma levels of noradrenaline, serum cortisol, free fatty acids, or blood glucose.

      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.

    2. In this test, endogenous depressives showed a significantly reduced HGH response to clonidine as compared to normal controls, neurotic-reactive depressives, and schizophrenics. However, no differences were found between the endogenous depressives and a group of schizoaffective patients.

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

    1. CONCLUSION: This meta-analysis confirms a medium effect (SMD = 0.62) of sleep deprivation on pain perception. As this meta-analysis is based on experimental studies in healthy subjects, the clinical relevance should be clarified.

      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.

  13. Oct 2018
    1. HFT increased lean mass by 1.06 kg ± 1.78 kg, (1.9%), and LFT increased lean mass by .99 kg ± 1.31 kg, (2.0%). HFT strength improvements on the chest press was 9.07 kg ± 6.33 kg, (11%), and hack squat 20.16 kg ± 11.59 kg, (21%). LFT strength improvements on chest press was 5.80kg ± 4.26 kg, (7.0%), and hack squat 21.83 kg ± 11.17 kg, (24 %).

      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.

    1. SWS was generally not affected. It is concluded that beta 1 neurotransmission is directly involved in the regulation of PS.

      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.

    1. Likewise, the significant (P<0.01) increases in mean cross-sectional area (and total muscle volume) were equal in both groups. Finally, strength increases were identical for both groups (PT=25% and NA=26% improvement). The results of this study suggest that muscle rebuilding – for example, hypertrophy – can be initiated independent of any discernible damage to the muscle.

      No benefit of pain.

    1. CONCLUSIONS: After 9 wk of training, the gains in both isometric and dynamic lifting strength were similar for the two arms. A single bout of damaging eccentric work did not enhance the response to conventional strength training and significantly compromised strength gains for several weeks.

      Pain = less gain.

    1. CONCLUSIONS: These data demonstrate improvement in FM-related sleep dysfunction with pregabalin therapy. The majority of this benefit was a direct effect of pregabalin on the patients' insomnia, while the remainder occurred through the drug's analgesic activity.

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

    1. Low BP was more prevalent in subjects with upper airway resistance syndrome (UARS) (23%) than in subjects with obstructive sleep apnea syndrome (OSAS) (0.06%), parasomnia (0.7%), restless leg syndrome (0.9%), or psychological insomnia (0.9%).

      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.

  14. Sep 2018
    1. Ritanserin, 5 mg, produced a substantially larger increase in SWS (51.4%) than either ketanserin, 20 mg (17.2%) or ketanserin, 40 mg (24.4%). Ritanserin has a significantly higher affinity than ketanserin for 5-HT2C receptor binding sites in the human brain and, based on estimates of per cent occupancy by the two compounds at brain 5-HT2A and 5-HT2C receptors, we conclude that SWS in humans is primarily regulated by 5-HT2C receptors.

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

    1. The use of a prospective sleep diary measure in patients with a psychiatric disorder is recommended.

      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.

    1. Analgesia obtained when 10 mg of morphine was combined with 100 mg of hydroxyzine was significantly superior to that obtained with morphine alone.

      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).

  15. Aug 2018
    1. CONCLUSIONS: These findings suggest that higher standing BP is a biomarker that helps identify persons with combat PTSD who are likely to benefit from prazosin. These results also are consistent with α1AR activation contributing to PTSD pathophysiology in a subgroup of patients.

      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.

    1. Dizziness or lightheadedness may be more likely to occur in the elderly, who are more sensitive to the effects of phenoxybenzamine. In addition, phenoxybenzamine may reduce tolerance to cold temperatures in elderly patients.

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

    1. In these two systems, the alpha 1 adrenergic receptor reappearance followed a monoexponential kinetic allowing to determine the half-life of the receptor (23h in vitro, 33h in vivo) as well as the rate of receptor synthesis and degradation.

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

    1. Typical half-lives are greater than 20 hr, a turnover that is slower than that of several other classes of neurotransmitter and hormone receptors (9, 10, 12, 16).

      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.

    1. Prazosin had no analgesic effect alone but dose-dependently potentiated morphine analgesia in morphine-naive mice. Another alpha(1)-adrenoceptor antagonist, corynanthine, had similar effects. Prazosin also increased the analgesic potency of the morphine test dose in morphine-tolerant mice. Naloxone-precipitated vertical jumping was not affected, but weight loss was reduced by prazosin. Acutely administered clonidine potentiated morphine analgesia and alleviated opioid withdrawal signs, as expected. We conclude that in addition to the already established involvement of alpha(2)-adrenoceptors in opioid actions, also alpha(1)-adrenoceptors have significant modulatory role in opioid analgesia and withdrawal.

      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)

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