322 Matching Annotations
  1. Feb 2020
    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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. May 2019
  7. 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.

  8. 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.

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    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.

  9. 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.

  10. 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.

  11. 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).

  12. 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)

    1. Graph 2 shows the trend for the diastolic pressure.

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

    2. Graph 1 shows the systolic pressure data (x-axis in mmHg). It can be noted that the test subjects start from an equal baseline condition, but after performing the swimming test the athletes not wearing the costume in the first control (20-30 mins) have an average systolic pressure that has dropped to approximately 90 mmHg.

      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.

    1. Table 2

      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.

    1. Hypertension also affects brain capillary density. Similar to the peripheral microcirculation, hypertension causes rarefaction (decrease in number) of capillaries and impaired microvessel formation that can increase vascular resistance

      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.

    1. Although atenolol had no effect on subjective measures of sleep this hydrophilic drug also reduced REM frequency, suggesting that either it has some central effect, or that REM reduction is due to a peripheral 'shielding' effect.

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

    2. Analysis of the subjective questionnaires showed that recollection of dreaming and awakening in the night was increased by the three lipophilic drugs, propranolol, metoprolol, and pindolol. These results confirm reports in the literature but are contrary to those expected from considering the effects of noradrenaline on sleep. Analysis of physiological records confirmed subjects' reports that waking was increased by the lipophilic drugs. Dreaming (rapid eye movement sleep, REM) was reduced, as predicted from knowledge of the effect of noradrenaline on sleep. Increased awakening leads to an increase in remembered dreaming which explains the otherwise paradoxical results.

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

    3. These results confirm reports in the literature but are contrary to those expected from considering the effects of noradrenaline on sleep. Analysis of physiological records confirmed subjects' reports that waking was increased by the lipophilic drugs. Dreaming (rapid eye movement sleep, REM) was reduced, as predicted from knowledge of the effect of noradrenaline on sleep. Increased awakening leads to an increase in remembered dreaming which explains the otherwise paradoxical results.

      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.

    1. Furthermore, no significant relationship (correlation coefficient: r < 0.3) was observed between beta 1 receptor occupancies of the drugs and the number of dreams. On the other hand, good relationships (r > 0.95) were observed between central and peripheral beta 2 or central 5-HT receptor occupancies and the number of dreams. These findings suggest that beta 2 and/or 5-HT receptor occupancy is superior to beta 1 receptor occupancy as an index for the sleep disorders.

      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.

    1. These results suggest that the combined use of mirtazapine mirtazapine Antagonist at: histamine, 5-HT2a/c, 5-HT3, a2(adrenaline. autoreceptor included) and prazosin may be a potentially effective treatment to attenuate induction and expression of locomotor sensitization to cocaine.

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

    1. AbstractHigh dose thyroid hormone has been in use since the 1930s for the treatment of affective disorders. Despite numerous papers showing benefit, the lack of negative trials and its inclusion in multiple treatment guidelines, high dose thyroid has yet to find wide spread use. The major objection to the use of high dose thyroid is the myth that it causes osteoporosis. This paper reviews the literature surrounding the use of high dose thyroid, both in endocrinology and in psychiatry. High dose thyroid does not appear to be a significant risk factor for osteoporosis while other widely employed psychiatric medications do pose a risk. Psychiatrists are uniquely qualified to do the risk-benefit analyses of high dose thyroid for the treatment of the bipolar I, bipolar II and bipolar NOS. Other specialties do not have the requisite knowledge of the risks of alterative medications or of the mortality and morbidity of the bipolar disorders to do a full risk benefit analysis.

      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

  13. Jul 2018
    1. Mg Citrate 0.26 ± 0.02 0.32 ± 0.03   0.33 ± 0.04*

      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.

  14. Jun 2018
    1. Studies reported by Nicoloff and colleagues in 1972 calculated a half-life of T3 that varied with thyroid status (8). The mean half-life was 0.63 days in 7 hyperthyroid patients, 1.0 day in 8 euthyroid individuals, and 1.38 days in 9 hypothyroid patients.
  15. May 2018
    1. Two patients complaining of insomnia had sleep-related periodic leg movements (nocturnal myoclonus) on polysomnographic evaluation. Both also complained of cold feet and had abnormal peripheral pulse examinations. Treatment with phenoxybenzamine, alpha-adrenergic blocker, normalized the peripheral pulse responses, reduced the complaint of insomnia, and reduced the sleep related leg movements but resulted in only mild sleep improvements. Peripheral pulse examinations of ten other patients with sleep-related periodic leg movements revealed abnormal responses in four. From these and other results, it is hypothesized that the sympathetic nervous system may mediate the periodicity of sleep related periodic leg movements.
  16. Apr 2018
    1. There was a boy who was born with congenital hypothyroidism and was raised on traditional T3 (Cytomel). He was never treated with a T4-containing medicine, and so essentially never had a molecule of T4 in his body. By age 26 he had developed normally with no problems.

      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.

    1. Naloxone alone has a bimodal effect on analgesia: low intravenous doses (1–2 mg) produce analgesia and higher doses (3+ mg) produce hyperalgesia in healthy normal volunteers (Buchsbaum et al. 1977) and in postoperative patients (Levine et al. 1979). Clinical trials showed that intravenous and epidural opioids combined with naloxone could produce greater analgesia than opioids alone (Rawal et al. 1986; Gueneron et al. 1988; Gan et al. 1997); these studies revealed the importance of the ratio of opioid agonist to antagonist in enhancing analgesia, showing ultra-low naloxone doses (ng/kg to pg/kg) are needed for optimal effect.

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

  17. Jan 2018
    1. Our findings indicate that equol diminishes estrogen-dependent tissue responses in apoE-null mice.

      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.

  18. Dec 2017
    1. Vegans had higher testosterone levels than vegetarians and meat-eaters, but this was offset by higher sex hormone binding globulin, and there were no differences between diet groups in free testosterone, androstanediol glucuronide or luteinizing hormone.

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

    1. Supposedly, Tianeptine, in contrast to other anti-depressants, stimulates release of neurotransmitter dopamine in nucleus Accumbens, that probably determine addictive potential of this drug.

      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.

    1. Gender socialization can direct some men to withhold or restrict emotional expression, leaving men with limited ways to express their feelings of emotional pain and psychological distress.

      ... 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

  19. Nov 2017
    1. Vegans had the highest intakes of fibre, vitamin B1, folate, vitamin C, vitamin E, magnesium and iron, and the lowest intakes of retinol, vitamin B12, vitamin D, calcium and zinc.

      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.

  20. Oct 2017
    1. basal testosterone (1.95 ng/ml)

      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.

    2. It is concluded that the severe cholesterol deficiency of this patient did not impair the capacity of the testes to synthesize testosterone. However, the LH/hCG receptor or its subsequent message was activated neither in vivo nor in vitro.

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

    1. We show that total testosterone peaks [mean (2.5–97.5 percentile)] at 15.4 (7.2–31.1) nmol/L at an average age of 19 years, and falls in the average case [mean (2.5–97.5 percentile)] to 13.0 (6.6–25.3) nmol/L by age 40 years, but we find no evidence for a further fall in mean total testosterone with increasing age through to old age. However we do show that there is an increased variation in total testosterone levels with advancing age after age 40 years. This model provides the age related reference ranges needed to support research and clinical decision making in males who have symptoms that may be due to hypogonadism.

      The remaining question is whether those with high testosterone in old age are the same as those with high testosterone in youth. That is to say, does testosterone diverge proportionally from the mean as one grows older, or are there other factors at play?

    1. Beta blockers have long been associated with sleep disturbances such as difficulty falling asleep, staying asleep, and insomnia. They have been shown to reduce the production of melatonin via specific inhibition of beta-1 adrenergic receptors. Melatonin is a hormone secreted by the pineal gland in the brain, and helps in maintaining normal circadian rhythms.6,20-21 People with hypertension already have a lower melatonin production rate than those with normal blood pressure.22

      The question becomes, then, do beta blockers impair sleep when exogenous melatonin is administered concurrently?

    1. A randomized, placebo-controlled, double-blind, cross-over study6 involving 16 patients with insomnia confirmed by polysomnography demonstrated no effects on sleep efficiency after a single 600-mg dose of the valerian extract Sedonium, while multiple doses over 14 days resulted in significant improvement in parameters of slow-wave sleep measured by polysomnography. There was a nonsignificant trend toward reduced subjective sleep latency after the long-term valerian treatment.6

      It appears that valerian may, after all, be beneficial for sleep when taken consistently. Personally, this in combination with the traditional use of valerian, and that valerian is likely harmless, is sufficient to merit use a recommendation (though emphaticism should be kept to a minimum). Additionally, the cases of contraindication (mentioned in another paragraph) could significantly enhance the magnitude of these results for those whom it worked. Those to whom it is contraindicated can self-select out of using valerian. In the context of a study, the remaining subjects should be re-randomized. For general application, valerian should be recommended to everyone, arming them with the information that it may be useless or detrimental for some people.