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The Anti-cortisol Effects Of Niacinamide

Discussion in 'Scientific Studies' started by haidut, Mar 1, 2016.

  1. haidut

    haidut Member

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    This is yet another confirmation of my suspicion that sedative substances lower cortisol levels. Niacinamide is officially recognized as a GABA-A agonist, but apparently this is not the major reason behind its effect on cortisol. The enzyme that de-activates cortisol - 11b-HSD2 - is apparently an NAD-dependent enzyme. On the other hand, the enzyme that converts cortisone into the active cortisol - 11b-HSD1 - is apperently sensitive to inhibtion by agents that are structurally similar to niacinamide.
    So, I has the thought that niacinamide would make the perfect anti-cortisol compound since it may be capable of BOTH inhibiting 11b-HSD1 and enhancing 11b-HSD2, thus BOTH inhibiting cortisol synthesis and enhancing its de-activation. Separately, inhibitors of 11b-HSD1 and enhancers of 11b-HSD2 are in clinical trials for a number of conditions associated with hypercortisolemia.
    After doing some more research, I found out that I am not the only one having these thoughts. In fact, the pharma company AstraZeneca has synthesized and patented (with very little publicity and fanfare) several derivatives of niacinamide that can directly inhibit 11b-HSD1 and has enrolled them in clinical trials for a number of conditions related to high cortisol including Cushing syndrome, diabetes, obesity, etc.
    I exchanged some emails with the lead author of these studies and he admitted that niacinamide may indeed inhibit 11b-HSD1 (by binding to it) and definitely will enhance 11b-HSD2 (by raising NAD levels).
    There is not much data on in vivo effective doses by the in vitro EC50 for the niacinamide derivatives is in the micromolar range, which means as little as 100mg niacinamide should do the trick.

    http://pubs.acs.org/doi/abs/10.1021/jm4014746
    Discovery of a potent, selective, and orally bioavailable acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor: discovery of 2-[(3S)... - PubMed - NCBI

    "...11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an NADPH dependent enzyme that is widely expressed, notably in liver, adipose tissue, and brain.10 It catalyzes the interconversion of the inactive glucocorticoid hormone cortisone (1) to the active glucocorticoid hormone cortisol (2) (Figure 1) and therefore plays a key role in the regulation of intracellular cortisol concentrations.11 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) is an NAD dependent oxidase expressed mainly in kidney and colon tissue that catalyzes the reverse reaction and prevents activation of mineralocorticoid receptors by 2.12 Inhibition of this enzyme has been associated with hypertension and other complications, and therefore, selectivity over this isoform is a key requirement for any potential therapeutic agent.13"

    "...Nicotinamide 4 had modest potency (IC50 = 350 nM) and was suprisingly unbound (rat plasma protein binding (PPB), 13.2% free) given the measured log D7.4 (3.2). Ligand efficiency was high as measured per heavy atom count (0.46) and moderate as measured by ligand lipophilicity efficiency30 (LLE = pIC50 − logD = 3.3). Sulfonamide 5 was more potent (IC50 = 200 nM) although less impressive in terms of ligand efficiency per heavy atom count (0.33) or ligand lipophilicity efficiency (2.8). The permeability of both was high as measured in a CACO-2 assay with no evidence of efflux."

    Nicotinamide uncouples hormone-dependent chromatin remodeling from transcription complex assembly. - PubMed - NCBI
    "...RT-PCR analysis of GR- and PR-regulated genes in the A1-2 cell line demonstrated that NAM also inhibits glucocorticoid dexamethasone (Dex)-induced GR-mediated transcription in addition to PR-mediated transcription (Fig. (Fig.1B1B)."


    A good synergy with niacinamide may be theanine and glycine, which also powerfully lower cortisol.
    Glycine Powerfully Lowers Cortisol | Ray Peat Forum
    Theanine Completely Abolishes The Cortisol Response To Stress In Humans | Ray Peat Forum
     
  2. ecstatichamster

    ecstatichamster Member

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    find a patented way to do what niacinamide does, and charge insurance companies for it.
     
  3. Kasper

    Kasper Member

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    Nice find :D
     
  4. PUTFOT

    PUTFOT Member

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    What kind of niacin to use and what dosage? Link me on Amazon.
     
  5. lollipop

    lollipop Guest

    Check out toxinless.com and see @Dan Wich's comparison of different brands. He links to Amazon.

    I vaguely recall Peat speaking about 50mg a day? Correct me anyone if I am wrong. I use 500mg once or twice a week.
     
  6. PUTFOT

    PUTFOT Member

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    Would taking niacin be enough to significantly lower serotonin?
     
  7. paymanz

    paymanz Member

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    Putfot I don't know about serotonin, but ray reccomends niacinamide,and not niacin.
     
  8. lollipop

    lollipop Guest

    Thanks @paymanz! I forgot to make that distinction/correction. I use niacinimide.
     
  9. PUTFOT

    PUTFOT Member

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    Ok. Thanks.
     
  10. HealthisWealth

    HealthisWealth Member

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    500mg once a week? Will a water soluble vitamins last in the body for weeks or excreted right away by the urine?
     
  11. Quality

    Quality Member

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    Wondering how well nicotinamide riboside (have been taken 500mg/day for the last 3months) would be in lowering cortisol, it is a far better NAD+ enhancer than all the regular forms of vitamin b3 (though far more expensive).
    I've found nicotinamide riboside one of the only things you can actually 'feel'.
    Might trial with niacinamide in the future, only other form of vitamin b3 that I've used standalone was nicotinic acid, and used that pre-bed, definatly got the flush and enhanced sleep of it.
     
  12. ecstatichamster

    ecstatichamster Member

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    many of us feel niacinamide/nicotinamide a LOT. Blood sugar tanks and it's pretty evident in dosages for me of over around 300mg.
     
  13. Peata

    Peata Member

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    It take 3 g. niacinamide a day lately without problems. I eat small meals over the day. I think the niacinamide is helping my mood a lot.
     
  14. Quality

    Quality Member

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    I personally have no experience with other forms of vitamin b3 other than nicotinicacid ( the flushing one ) pre-bed.
    Well besides my b-100 supp that I used in the past containing a fair amount, but that obviously had high dose of other b-vitamins in it aswell, so it would be impossible to track how much of an effect the vitamin b3 in it would have on me.
    Also @ecstatichamster, how do you dose your niacinamide, all at once? time of the day?
     
  15. Quality

    Quality Member

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    Holy ***t 3grams, do you have high cholesterol?
    And arent you concerned about possible insulin resistance?
    Vitamin B3 - Scientific Review on Usage, Dosage, Side Effects | Examine.com
    Current evidence suggests prolonged niacin supplementation increases insulin resistance because it hinders the ability of insulin to suppress glucose synthesis in the liver. This causes an increase in blood glucose levels, which leads to lowered insulin sensitivity over time, since the relevant receptor is eventually desensitized to the elevated glucose levels in the blood.
     
  16. Peata

    Peata Member

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    No. I'm not taking this much long term. Eventually plan to go down about half the dose.
     
  17. Quality

    Quality Member

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    Even 1.5gram seems a whole lot, and i mean ALOT.
    Once again ill ask, what are you taking it for or trying to achieve?
     
  18. Peata

    Peata Member

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    Reduce serotonin, cortisol, estrogen, phosphate, lactate, mild but annoying joint pain in wrist, improve mood, energy, metabolism, skin.
     
  19. sugarbabe

    sugarbabe Member

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    It is not a lot. That is a therapeutic dose and is quite safe. As long as you aren't getting extremely cold from it.
     
  20. lollipop

    lollipop Guest

    I experimented with 1.5gm day before yesterday and felt great tbt. In fact I think it reduced some inflammation and a slight discomfort sort of like reflux for about a week disappeared and has not returned. I took 1.5gm again this morning about an hour ago. Am watching...
     
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