220 Matching Annotations
  1. Last 7 days
    1. Ritanserin was highly effective in reducing Pain Total Index and analgesic consumption in chronic headache, and its activity was similar to that observed during amitriptyline treatment. A significant improvement of HRSD and HRSA(Hamilton Rating Scale for Anxiety) scores was observed during both treatments.

      This may mean ritanserin is superior. Amitriptyline is a dirtier drug affecting more than just serotonin receptors. Therefore, ritanserin likely has fewer side effects. However, I'm not currently aware of any studies demonstrating this.

  2. Apr 2021
    1. Stolen Childhood (2019)

      30:55 Ibuprofen rescue. Interesting concept, though I am somewhat skeptical.

    1. What you Need to Know about Loneliness

      18:03 Loneliness leads to microarousals. Could this be a potential root cause of ME/CFS.

    1. Day 2: extremely difficult. My brain was convincing me time and again to light one . It was trying to convince me that i Needed one. Almost lit one but put it down. It felt like i had gulped down a pre workout or a protein shake and had not worked out. Felt frisky and restless. Dependent on a vape - 9/10

      Sounds like withdrawal. Why is information like this so hard to find?

    1. In seven out of the eleven subjects in whom core body temperature could be sampled, the nadir of body temperature was advanced during L-T4 intake by 15 minutes to 270 minutes.

      This supports my speculation from another study, found here.

    1. However, coadministration of nefiracetam (5 or 10 mg/kg, p.o.), enprofylline (30 mg/kg, p.o.) and rolipram (0.3 or 1 mg/kg, i.p.) with morphine during the pretreatment period, significantly reduced the withdrawal signs, moreover, the tolerance was significantly attenuated.

      Looks promising. It's odd that theophylline had a lesser effect.

    1. Conclusion: Our data suggest that the combination of VLF with morphine may be a relevant therapeutic implication to manage pain even when tolerance to morphine exists. Moreover, our data demonstrates the involvement of L-Arg/NO/cGMP pathway in the prevention of morphine tolerance and dependence by venlafaxine.

      It's not clear if this has relevance to the subjective effects. I'm starting to think that I won't get an answer anytime soon.

    1. Sildenafil treatment enhanced the development of tolerance to the motor impairing effects, but not to the sedative effects, of DZ.

      I'm not sure what conclusions I should draw from this.

    1. Results: The administration of sildenafi l reduced all of the morphine withdrawal symptoms.

      An acute effect. Interesting but not particularly consequential. It does mean, however, that I need to be wary of studies using withdrawal as a netric when combining PDE5 inhibitors with opioids.

    1. Results: Tadalafil showed anti-nociceptive effect when given alone at different doses (p<0.05). However, tadalafil significantly decreased the analgesic effect of morphine (p<0.05). In addition, tadalafil significantly increased the tolerance to morphine (p<0.05). Conclusions: The phosphodiesterase type 5 inhibitor tadalafil have anti-nociceptive properties and it decreases analgesic effect of morphine, in addition improves tolerance development. These effects probably may occur via NO/cGMP pathway.

      This is analgesia, so is not necessarily relevant for my purposes. Nonetheless, there implies some relevance of cGMP, but the direction isn't yet clear.

    1. Repeated KOR agonist exposure, on the other hand, can result in opposing effects on the dopamine system [27], and desensitization of the KOR [28]

      If they mean what I think they mean, then this implies that chronic KOR is useful. I'll need to check citation 27.

    1. These data suggested that PAT, an indirect-acting KOR agonist, share the common pharmacological property of KOR agonists on morphine tolerance

      PAT is apparently an herbal medicine I should look into. They also imply that KOR agonists act as I expect they do, but I'll need to read the full study to be sure.

      Edit: yup, it appears that chronic KOR agonism is probably a good idea.

      from full text "Utility of KOR agonists is a promising pharmacological tool for attenuating morphine tolerance (Pan, 1998), however, it is difficult to find effective KOR agonists that are devoid of dysphoric and psychotomimetic adverse effects in humans"

      This is the cited study.

    1. Oral nimodipine (120 mg.day -1 ) was noted to significantly reduce the daily requirement of mor­phine, provided the patients have been already on mor­phine therapy for some period of time.

      Interesting. It is not clear the ideal time/order of administration.

    2. The results also showed that diltiazem was able to selectively potentiate the analgesic effect of morphine but not of fentanyl (the reason was not known).

      Fascinating. However, this provides no insight into the subjective effects. However, it does reduce my certainty that any given combination of drugs (sharing these mechanism) will work. There doesn't seem to be consistent results with these L-CCBs plus opioid studies.

    1. The results suggest the euphorigenic and analgesic effects of opioids may be differentiated by using Ca++ channel blockers.

      Yes. That also means that most of the rat studies I've been reading are useless for my purposes.

    2. however, 10 mg of verapamil significantly reduced morphine-elevated MBG scores over a 3-hr period.

      That's a shame. I still need to find out the long term effects on mood. There seem to be only three human studies on calcium channel blockers combined with opioids. I infer that from google search results plus the review that lead me here.

    3. MBG scores

      Morphine Benzedrine Group (ARCI-MBG) scale was designed to measure benzodiazepine-induced mood elevation.

      https://pubmed.ncbi.nlm.nih.gov/11417943/

    1. Administration of L-CCBs alone, particularly diltiazem, increased pain in the formalin test. In contrast, co-administration of these L-CCBs with morphine led to decreased pain response

      There is still the question of subjective effects. Given that I'm primarily interested in this combination as a psychological treatment and as a transhuman upgrade, increased pain is not a deal-breaker. It's also not quite clear how this holds up in the long term. That is, do the effects of L-CCBs on pain change after supersensitization to opioids?

    1. Treatment with both morphine and forskolin appeared to cause an additive effect in desensitizing mu-opioid receptor.

      This is getting very odd. It is hard to draw useful conclusions. This is partly because I'm out of my depth.

    1. Theophylline (2.5-100 mg/kg) in combination with morphine (5 mg/kg), during conditioning sessions, decreased the acquisition of morphine conditioned place preference dose independently. Administration of theophylline (2.5-100 mg/kg) before testing also caused a significant reduction of the expression of morphine-induced conditioned place preference in a dose-independent manner.

      Shame. It may prevent tolerance partly by reducing the subjective effects. Though, there are other possible explanations.

    1. Future studies should be conducted to test if the decreased cortical brain activity after nimodipine is associated with improved working memory performance in patients with schizophrenia, particularly those who carry the risk-associated genotype.

      Interesting hypothesis.

    1. Results:Nimodipine when administered as a single bolus dose before naloxone administration in morphine-dependant rats reduced the features of withdrawal reactions more effectively than continuous administration of nimodipine along with morphine throughout the experimental period.

      Weird and surprising.This plausibly implies that L-type calcium channel blockers may not be as effective as it first appears.

    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).

      Consistent with rat data. This is from 1998. I'm sure there's more evidence by now. It's been a while since i researched this, but I think I've previously seen at least one other study.

    1. These results suggest that the elevation of the cyclic AMP levels is involved in the development of morphine withdrawal syndrome and that blockade of the morphine-induced reduction of cyclic AMP levels by chronic rolipram inhibits the development of dependence and the behavioural and biochemical changes induced by naloxone. Furthermore, rolipram may be a useful drug for attenuating the development of morphine dependence.

      Excellent. This implies that theobromine may help prevent opioid tolerance.

    2. However, acute rolipram did not affect the naloxone-precipitated morphine withdrawal syndrome.

      Worth noting.

    1. Humans can easily digest and excrete methylxanthines, the half life of theobromine being 2-3 hours.

      That is absurdly shorter than other citations. It is almost certainly wrong.

    1. Bleuler defined schizophrenia with his four ‘A’s’, referring to the blunted Affect (diminished emotional response to stimuli); loosening of Associations (by which he meant a disordered pattern of thought, inferring a cognitive deficit), Ambivalence (an apparent inability to make decisions, again suggesting a deficit of the integration and processing of incident and retrieved information) and Autism (a loss of awareness of external events, and a preoccupation with the self and one’s own thoughts)

      I stumbled upon this accidentally. I was going to add to my prediction that schizophrenia might be related to autism, but now that I've found this I need to publish my draft.


      Edit: Here was the prediction I wrote. Copied unmodified, ensuring transparency.

      March 28, 6:15pm Prediction: Some cases of schizophrenia are being misdiagnosed as autism. I recently took a Coursera.org course on schizophrenia. The negative symptoms look similar to some autism symptoms.

      Before I look it up, there are a few other predictions I should make. Do I think schizophrenia and autism will be linked? If there’s cross-diagnosis, will this link be artificial or real? Last time I looked, people with aspergers had (more or less) normal sleep EEGs. In contrast, schizophrenia is associated with disrupted sleep spindles. I already know that schizophrenia and bipolar are genetically linked, but I don’t know what the bipolar sleep EEG looks like. That is to say, I don’t know if the lack of sleep abnormality in autism is evidence against a link to schizophrenia. All in all, I predict that there will be a real link (for example, genetic), but I have a low confidence in this prediction. The reason is that I expect there is little EEG sleep changes in bipolar, implying that there is a supra-mechanism causing all these effects; somewhat like metabolic syndrome, the same cause may manifest in different ways.

    1. After World War II, many antioxidants were found to protect against the harmful effects of ionizing radiation when administered prior to exposure.

      Both interesting and completely unsurprising. However, I'm curious about protection against fission specifically. That is to say, can we protect against existential risk by nuclear weapons by stocking nuclear bunkers with antioxidants.

    1. Using this data, a large international team was able to pinpoint 114 specific loci – locations in the human genome – that contribute to risk of both schizophrenia and bipolar disorder, and four genome regions that contribute to differences in the biology of the two disorders.

      This is exactly what I expected. In fact, I would have been extremely surprised if this weren't the case. I just google "schizophrenia bipolar genes" expecting this result.

      I had the thought a few minutes ago, and google it right away. This means that I wasn't able to write it down as a prediction. Nonetheless, I think this points in favor of my prediction abilities. My confidence was inordinately high (i.e. on the order of 90%) even before collecting any evidence. Compare that to other high confidence beliefs (e.g. CFS is caused partly by blood volume), for which I have confidence on the order of 95%, but I have good evidence for that belief. Thus, this instance provides data that my confidence meter is reliable. I'll continue to make an effort to write down predictions ahead of time (to eliminate publication bias).

      There are several reasons I suspected this would be the case. Firstly, personal subjective experience; that's what gave me the first inkling. Secondly, the connection of mania with long periods of sleeplessness. If the sleep deprivation causes the mania, then bipolar may be a sleep disorder. This is backed up by the sleep deprivation therapy for depression. Additionally, the connection of depression to sleep disturbance implies that sleep may also be causal in low mood. Furthermore, given that schizophrenia is associated with disrupted sleep spindles, it follows that the two sleep disorders, namely schizophrenia and bipolar, may be closely related genetically (via sleep regulating genes). Moreover, I knew that schizophrenia and bipolar were two of the most heritable psychological conditions; given that both are highly genetic and both involve sleep, it follows that they would likely be closely linked. Finally, I know mania can be associated with delusions, so there are several symptom crossovers. All in all, it is highly surprising that I have not seen this discussed before. Neither documentaries on schizophrenia nor documentaries on manic depression/bipolar have mentioned a link. Nor have studies I've read (admittedly few on this particular topic) mentioned anything of the sort. I shall have to look through the literature to see if this idea has been around for long.

    1. with almost no change in psychosis

      I almost counted this as a point against my prediction, but then I realized this is an acute effect. Positive symptoms do appear to benefit from exercise.

    2. This study explores motivational parameters and subjective experiences associated with sustained, independent exercise in outpatients with a diagnosis of schizophrenia or schizoaffective disorder.

      What an interesting objective. I think that relying on patient report is more effective than people realize.

    3. The prospective ratings demonstrated 10–15% average improvements in global well-being, energy, and negative, cognitive and mood symptoms, with almost no change in psychosis, after individual exercise sessions.

      Fascinating that there are acute benefits (presumably in addition to chronic benefits). Given that negative symptoms in particular are resolved, it may simply be stimulating effects.

    1. Exercise can tackle symptoms of schizophrenia

      Not only am I unsurprised by this, but I'd be surprised if it were otherwise. The logic is that schizophrenia is a sleep disorder, and exercise enhances sleep. Additionally, lack of movement is one of the negative symptoms of schizophrenia. Therefore, this poverty of movement may play a role in the pathogenesis of schizophrenia symptoms.

      I need to start a google search document with predictions prior to actually searching. It will slow down my research speed, but it is necessary in order to provide unbiased data on my intuitive understanding of diseases. It seems like the majority of my strong intuitions are true. Edit: I'll just record the search phrase in my hypothes.is notes. This one was "exercise schizophrenia"

    2. The areas which were most improved by exercising were patients' ability to understand social situations, their attention spans, and their 'working memory'

      That is an interesting set of improvements. These are negative symptoms that are resolved, which is largely what I'd expect. I'd bet there is some effect on positive symptoms too, but with low certainty. Moreover, these results are excellent in that negative symptoms are the hardest to treat.

    1. How Catching Covid Can Change Your Personality - Dr Diana Fleischman | Modern Wisdom Podcast 290

      41:20 Influenza caused an uptick in schizophrenia. Given context, it sounds like she's talking about the mothers catching the flu during pregnancy.

  3. Mar 2021
    1. The decrease in total activity count and phase delay of onset of the activity rhythm caused by ethanol were partially antagonized by theophylline.

      I think the takeaway is that theophylline may help with phase delay. Though, that is merely my thoughts at first glance. Not to mention that this is rat data. Nonetheless, combining this with data on the cAMP and cGMP role in circadian rhythm, I'm relatively confident that methylxanthines have some effect on circadian rhythm. Most likely phase advancing effects.

      In practice, this means theobromine should be explored as a treatment for Delayed Sleep Phase syndrome (DSPS). It may also be useful for some non-24 conditions. I may consider upping my theobromine dose so that I can get to sleep early and wake up early.

      Also, perhaps I should avoid ethanol in the morning. Hard to say from this data.

    1. Julia Galef Discusses Intellectual Honesty

      28:42 yale professor dan kohan. Scientific literacy among democrats and republicans made empirical polarization worse on issues like climate change. Scientific intelligence makes polarization worse, but scientific curiosity lessons polarization. Note that the effect was significant but not staggering.

  4. Jan 2021
    1. On the other hand, in the process of roasting such polymeric compounds as melanoidins (which are potent antioxidants) and other compounds are formed.

      This is more evidence that cooking is neutral or positive, provided temperatures are not excessive. I doubt this would convince raw foodists, but it may.

    1. IC50 values for histamine-H1, dopamine-D2, and adrenergic-alpha 1 and -alpha 2 sites were 39-, 77-, 107-, and 166-fold higher

      Thus, ritanserin is highly selective for 5HT2 receptors. By comparison, ketanserin antagonizes.adrenergic alpha 1 in addition to serotonin receptors.

    1. Recipe from Use soy-bean flour to save wheat, meat, and fat (Washington, DC: U.S. Dept. of Agriculture, Office of the Secretary, 1918). 

      I'm intrigued by wartime cookbooks. This is exactly the type of recipe I'm looking for. It looks versatile, cheap,and simple.

    1. Analyses using the scale that included alternative and traditional depression symptoms found that men and women met criteria for depression in equal proportions: 30.6% of men and 33.3% of women (P = .57).

      According to the CDC, the lifetime risk of depression is about 1 in 6. Adding this new criteria nearly doubles that to 1 in 3.

      These new criteria detect depression at a rate of roughly 1 in 4. That's a higher rate than the standard test, but it doesn't detect all the cases of depression.

    1. dopamine acetylcholine, serotonin, gamma aminobutyric acid (GABA), cannabinoid and vanilloid among others.

      This was published in 2007. I'll see if I can find later research. It may be that oleamide is a mystery drug like modafinil.

    1. Moreover, the action of oleamide most relevant to sleep induction involves, in part, cannabinergic pathways, as evidenced by the ability of the cannabinoid antagonist SR 141716 to inhibit the hypnotic actions of OA.

      I'm not convinced that oleamide works via cannabinoid system. In support of CB involvement, I found a study showing that CB1 antagonism does not alter sleep. However, I'm unable to find the effects of CB1 antagonists combined with benzos. I suspect a CB1 antagonist will partially block the effects of hypnotics. If that's the case, then the fact that SR141716 has this effect would not imply cannabinoid involvement by oleamide.

    2. Nonetheless, enhancement of cannabinergic function may not be the only mechanism by which OA alters sleep, as it can act synergistically with subthreshold doses of triazolam (0.125 μg) to reduce sleep latency.

      I'm moderately certain that cannabinoid receptor agonism is not the primary mechanism. However, I'll need to check whether THC synergizes with benzos to see if their logic holds up. I bet it doesn't follow (meaning I expect THC to synergize).

    1. Transformation of chavicine to piperine can be seen on storage

      I don't know why I had such a hard time finding a citation for this. A couple years ago I had read that the piperine content of pepper increases during storage. I had used this as an example of why degradation isn't necessarily a bad thing, but rather it depends on what it is being degraded to.

      I was beginning to question whether this was a real thing. Now that I wasn't looking for it, here I find it. I was actually searching for proper storage of piperine. That is, how should I store it if I buy large quantities.

  5. Dec 2020
    1. Turmeric Spice, Ground

      They are 10 times off based on several samples from this study. Turmeric only has 10 to 15 thousand ORAC, not 127 thousand. This error is likely either a typo or they are citing the value of curcumin rather than turmeric.

      See here for google sheet version of study cited above.

      EDIT: I checked their source. They appear to have represented the source accurately. Why, then, the ten fold difference?

    1. The 5-HT2 antagonists reportedly produce a paradoxical down-regulation of 5-HT2 binding sites upon chronic treatment, rather than the expected supersensitivity. Chronic treatment with ritanserin (2.5 mg/kg/day for 7 days), but not mianserin (same regimen), attenuated a QMWS 24 h after the final injection, thus supporting with a functional measure, the down-regulation of such binding sites by ritanserin.

      Are they saying that mianserin did not downregulate the receptors? That's what it sounds like. Most likely this is just because it is a weaker antagonist than ritanserin.

    1. In contrast, ritanserin did not impair driving performance or affect objectively measured daytime sleepiness, while subjects reported to feel more alert during daytime.

      Fascinating. This increased subjective alertness is probably due to enhanced sleep.

    1. similar effects were demonstrated by placebo as well.

      That's concerning. Note that the treatment group performed ever so slightly better than placebo. I'm guessing that that is either due to random chance, or a benefit that any anti-inflammatory plant may provide.

      I'd be curious to know why nettle. The authors of this paper seem to think it is the anti-inflammatory and antioxidant activity. However, they are merely following up on past research. They mention that nettle has been used worldwide as an alternative medicine. Therefore, the original research may be based on the traditional uses of the plant.

      If nettle does in fact work, I see three possibilities. Nettle may have unique benefit that this study wasn't powered enough to find. Nettle may may have benefit that any plant anti-inflammatory plant would have. Finally, they may not have been using nettle properly.

  6. Nov 2020
    1. If the light is not quite so bright, chronic exposure over days to weeks can cause permanent damage. This is thought to be due to what is called photo-oxidative damage

      Just as one would expect, it appears that antioxidants can protect against this type of damage. Note that the study was in rats, but we have every reason to think it would work in humans. In particular, several studies showing that dietary antioxidants protect skin from sunlight in humans; it's should be essentially the same thing for the eyes.

    1. Rosemary enhanced the protective efficacy of AREDS and led to the greatest effect on the retinal genome in animals reared in high environmental light. Chronic administration of rosemary antioxidants may be a useful adjunct to the therapeutic benefit of AREDS in slowing disease progression in AMD.

      This is not in the least surprising. Dietary antioxidants also protect the skin during sunlight exposure.

      Oxidative stress likely also plays a role in diabetic retinopathy. It plays a role in the aging process itself. That said, there is probably a limit to protective powers of antioxidants. Nonetheless, I don't think that that limit has ever been realized in any population. I doubt we've even come close in rats.

    1. between themethionine synthase apoenzyme and oxidizedvitamin B12 may be broken. It is to be expected thatany Blt preparation administered during exposureto nitrous oxide would be rapidly oxidized tobivalent cobalt.

      That's what I assumed from other readings. Why, then, can I only find studies administering B12 near the time of the surgery? Those studies still found protective effects on homocysteine elevation, but that may be mostly due to the coadministered B9.

      This means B12 should be taken either well before NO, or sometime after. Given the short half life of NO, it should be fine to take B12 orally immediately after a final NO dose; the B12 will be absorbed shorty after the NO is eliminated.

    2. The required dose in man is large.However, there is now very strong evidence that30 mg twice daily will prevent development of anabnormal dU suppression test and megaloblasticmarrow changes in some, but not all, patientsduring prolonged exposure to nitrous oxide

      I will need to check out the sources. Perhaps B12 status is the difference between said patients?

    1. Fig 1

      Note that, though folate and B12 were given IV before and after surgery, it did not have an immediate effect. The NO induced rise in homocysteine was not blunted by the end of surgery. However, postoperative homocysteine was lowered to below baseline on all 3 measurement days. The NO induced rise in homocysteine lasted 2 days postoperatively.

      Unsurprisingly, this suggests a lag time between B vitamin administration and homocysteine drop. Thus, what I'd really like to see is a study administering B vitamins 1 day prior to NO use.

    1. This inhibition was completely reversible by addition to the culture medium of pteroylglutamate and 5-formyltetrahydropteroylglutamate and partly reversible by cyanocobalamin.

      This suggests those taking NO should supplement with both B9 and B12. It is likely that the effects on B9 are more acute, while B12 deficiency probably only becomes an issue with chronic abuse or in those with borderline B12 status to begin with.

    1. Acai Berry Pulp/Skin/Puree Powder

      I found a study on acai and blood sugar, but they used healthy overweight subjects. The relative reduction in postprandial glucose was substantial. However, since the subjects' baseline fasting glucose was normal, the drop was not significant. We have every reason to think that fasting blood sugar would be reduced in diabetic subjects.

    2. Baobab Fruit Powder, Dried

      I was unable to find a study on baobab on diabetes or metabolic syndrome. However, given the effectiveness of amla, curcumin, and acai, it is likely effective. There is also some evidence for many other antioxidant sources, which backs up the idea that any source will do.

    3. Sumac Bran, Raw

      I've found one study on sumac for type 2 diabetes. There seems to be two separate write-ups on the same data.

      Oddly, 3 grams sumac did not perform as well as 3 grams amla. I can think of several possible explanations. The most likely explanation is that they used the whole grain rather than the bran. I assume the grain is what's used traditionally, but I'm having difficulty finding information about this. The bran has over 3 times the ORAC compared to the whole grain. It's likely that the bran is both hard to find and expensive.

    1. Curcumin, but not fish oil, reduces postprandial glycaemic response and insulin demand for glucose control.

      This backs up the two studies on fasting glucose in diabetes and per-diabetes. It is also a higher quality study (crossover design).

  7. Oct 2020
    1. For Burger Patties8 ounces (225 grams) mushrooms 1 medium carrot 1 1/2 cups (85 grams) broccoli florets 1/4 medium onion 2 medium garlic cloves 2 tablespoons (30 grams) oil such as olive oil, avocado oil or grape seed, plus more for cooking 1 teaspoon smoked paprika 1 teaspoon chili powder 3/4 teaspoon fine sea salt 1/4 teaspoon fresh ground black pepper 1 (15-ounce) can black beans, drained and rinsed 1/3 cup (35 grams) walnut halves (about 14 halves) 2 cups packed (85 grams) spinach leaves Handful tender fresh herbs like chives, parsley or cilantro (optional) 1/2 cup (100 grams) panko breadcrumbs 2 large eggs 1 tablespoon (15 grams) tomato paste 3/4 cup (115 grams) cooked brown rice Bread rolls, lettuce, tomato, cheese and favorite burger sauces

      Looks good. I will be using slightly crushed black.I'll use ground chickpea to thicken the water into a patty (along with the flax egg). I'll saok all ingredients in water for 24 hours. Then I'll remix and cook.

      I'll be cooking in a cylindrical contanter (inside pressure a cooker), then cutting it into burger slices. It will likely get stuck to the container, but I can't think of a surefire way to make it not stick given that it will start out as a soup that hardens. I could try a pre-cooked slice of something oily (such as oily bread, for example).Lining the bottom of the container with that could do the trick. I'll just cut around the sides, then pull out the cylinder.

      EDIT: I just realized I can use a cooking cylinder. It has no bottom, so I'd just have to lift it up, cut around the edge, and push it out. I'll make a thick sludge prior to cooking (by using flax), to minimize leakage. I'll place it inside a bowel with a small pool of oil. Even if it sticks, it won't matter because I can neatly tear or cut both dimensions (bottom and sides) without deforming my patty block.

    1. Ingredients10-12 oz. of tomato paste10-12 oz. of tomato paste1/8 - 1/3 cup of apple cider vinegar or white vinegar add 1/8 cup first - the full 1/3 makes a tangier ketchup (which we like). If you want more tang, add a little more at a time. White vinegar can also be used.1/8 - 1/3 cup of apple cider vinegar or white vinegar add 1/8 cup first - the full 1/3 makes a tangier ketchup (which we like). If you want more tang, add a little more at a time. White vinegar can also be used.1 tablespoon of sugar1 tablespoon of sugar1/2 teaspoon salt1/2 teaspoon salt1/4 teaspoon black pepper1/4 teaspoon black pepper1/2 teaspoon mustard powder1/2 teaspoon mustard powder1/2 teaspoon dried oregano1/2 teaspoon dried oregano1/2 teaspoon cayenne1/2 teaspoon cayenne1/2 teaspoon onion powder1/2 teaspoon onion powder1/2 teaspoon of garlic powder1/2 teaspoon of garlic powder1/4 teaspoon celery salt1/4 teaspoon celery saltpinch of ground all spicepinch of ground all spice

      Tasty! I trippled the sweetener content to nearly match comercial ketchups (using erithritol, stevia extraxt, and monk fruit extract).

    1. Breads containing 30% and muffins containing 50% flaxseed were rated better than their counterparts regarding overall acceptability scores.

      That is a surprisingly high level. It's worth noting that 30% is the highest level tested in bread, so the highest level tested was the best. Given that they tested muffins up to 66%, it seems plausible that the 50% found optimal in muffins may also be optimal in bread.

    1. 1/4 cup (60 mL) ground flax3/4 cup (175 mL) warm water1/2 tsp (2 mL) salt2 tsp (10 mL) canola or flax oil1 3/4 cups (425 mL) all-purpose flour (approx)

      I calculate that that's a flax content of about 18 baker's percentage.

    1. The unique Umami characteristic of Dried Shiitake is Guanylate. This Umami component is created during the drying and rehydrating process, and not available in Fresh Shiitake.

      Interesting. This makes it likely that shiitake extract is the type of mushroom used in mushroom seasoning or takii. Most products just say "mushroom powder" and "mushroom extract". Some products list "shiitake powder" and "mushroom extract". I can find no product listing the type of extract used.

      Edit: The linked table shows dried shiitake has the highest guanylate and glutamate of the listed mushrooms. Given that the website is about umami generally, this dramatically increases the odds that it is shiitake extract used in said products. It implies that dried shiitake may be the most umami mushroom (though no other dried mushroom is listed).

    1. Cessation of nitrous oxide resulted in characteristic convulsions similar to those seen in alcohol withdrawal in all mice.

      This demonstrates that tolerance is possible. However, exposure in humans lasts only several minutes at a time. Let's assume 3 exposures per day lasting 10 minutes each (i.e. 30 minutes total). It would take 68 days to reach 34 hours of exposure. Alternatively, that's a ratio of 1 to 47 exposure to non-exposure. It's unclear whether that would be sufficient for tolerance.

      In the 50% exposure group, convulsion score was effectively zero by hour 6 (from full text). This does not mean that withdrawal symptoms were gone. However, it does imply that recovery is rapid. It seems plausible that 20 hours between doses is sufficient to reach baseline, rendering tolerance in humans extremely unlikely. I will need to compare to alcohol withdrawal to confirm.

      Edit: Alcohol withdrawal in mice can be induced with 72 hours of alcohol exposure. That implies it is similar to NO. In humans, "the shakes" appear to last 1 or two weeks. In mice, convulsions appear to be half gone in 25 hours, suggesting that they last a few days. Thus, it appears that NO withdrawal is possibly an order of magnitude shorter than alcohol withdrawal.

      In conclusion, NO used in a normal fashion is unlikely to be harmful (except for risk of inducing B12 deficiency). Even if it is harmful, the short half life means that it will be apparent very quickly. I'm aware of several reports of B12 deficiency from NO abuse, but I haven't seen any reports of withdrawal symptoms.

  8. Sep 2020
    1. THC-piperine-PNL which resulted in a 9.3-fold increase in AUC as compared to THC solution.

      While this is impressive, it doesn't mean ten times the effect given that the active metabolite is being limited by the piperine. It does, however, suggest that oral bioavailability of THC can potentially be on par with or superior to pulmonary administration.

    2. Here we use piperine, curcumin and resveratrol to formulate the Advanced-PNL formulations.

      I'll need to read up on why they used curcumin and resveratrol. I was also planning to use curcumin because it stimulates bile release. That may be their reason as well. They used piperine because it inhibits p450 enzymes. I'm not sure why they might have used resveratrol, though I do recall hearing that it is a bioenhancer.

  9. Aug 2020
    1. It appears therefore that the labeled vitamin was absorbed from the large intestine, perhaps by non-specific passive diffusion. Similarly, vitamin B12 synthesized in the large intestine by microbial flora could gain access to the tissues by such a mechanism. The possible role of intestinal vitamin B12 of microbial origin in rats, and perhaps in man, and factors affecting the utilization of this vitamin are discussed.

      This provides some reason to be agnostic as to whether vegans can obtain B12 naturally. Of course that shouldn't matter to any rational person (who'd just take a supplement). Note that I was searching for this info, and this is the first piece of evidence I found. Thus, I suspect there is more evidence since 1965. I'll try to tag updates with "nativeB12"

    1. However, even moderate intake places women at higher risk for breast cancer and bone fractures

      This minimizes the chances that the benefits are due to abstainer bias. Nonetheless, I'm finding it hard to verify that there are benefits to low dose alcohol.

  10. Jul 2020
    1. Can Boost the Effects of Stimulants Clonidine can be prescribed in addition to a stimulant medication, which often enhances the effectiveness of the stimulant.

      Will need to read up on that. Is that just for ADHD, or other conditions as well?

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.