haidut

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I posted several studies on aspirin and sodium salicylate being effective in reversing insulin resistance and type II diabetes in humans. However, to my knowledge the mechanism of action of aspirin and other prodrugs for salicylic acid has never been publicly elucidated even though Ray has written extensively about the various benefits of aspirin on metabolism such as opposing estrogen, histamine, serotonin, prolactin, etc.
This study now adds another benefit to aspirin that I hinted towards in another post of mine - i.e. it seems that aspirin is able to also lower cortisol synthesis, and it has been confirmed in humans. The mechanism of action is inhibition of the enzyme 11β-HSD1, which is responsible for the conversion of inactive cortisone into the active glucocorticoid cortisol. A few other substances that are capable of doing this include emodin, niacinamide, vitamin A (retinoci acid) and zinc. However, the list of sunstances that have been shown to lower cortisol in humans also includes glycine, theanine, taurine, magnesium, thyroid, vitamin E, vitamin B6, vitamin B1, etc.
The study used both an animal model and humans. The drug used for the animals was sodium salicylate and for humans salsalate was used instead. Why they used different drugs I am not sure, but both of them are pro-drugs for salicylic acid. What is also surprising is that the human equivalent dose in the animal model was about 10mg/kg of sodium salicylate for 4 weeks, which equates to about the same dose (10mg/kg) of aspirin. In the human study they used 1g salsalate every 8 hours for 2 weeks, so 3g salsalate total daily. Converting to aspirin, this means about 4g aspirin daily to obtain the same amount of salicylic acid. The human study I posted for aspirin lowering cortisol used 800mg twice a day. So, the evidence suggests anywhere between 1g and 4g aspirin daily should have a peripheral cortisol lowering effect, and the dose likely depends on how much cortisol needs to be lowered. In people with diabetes II and high peripheral cortisol levels, as much as 4g of aspirin daily may be needed. In people with normal insulin sensitivity and occasional stress exposure, 1g aspirin may be enough.

Salicylate downregulates 11β-HSD1 expression in adipose tissue in obese mice and in humans, mediating insulin sensitization. - PubMed - NCBI

"...Sodium salicylate (salicylate) (120 mg/kg/day) or distilled water (vehicle) was administered from 1 week after arriving (C57Bl/6 Lean), after 10 weeks of high-fat feeding (C57Bl/6 DIO), or after achieving target weight (HSD1KO-DIO) for 4 weeks to groups of n = 8 via osmotic minipumps implanted subcutaneously between the scapulae."

"...A total of 16 otherwise healthy men, selected to represent a wide range of BMIs, from 20 to 50 kg/m2, took part in a double-blind balanced randomized crossover study to compare salsalate (Disalcid; 3M Pharmaceuticals, Northridge, CA; 1 g p.o. every 8 h for 2 weeks) with placebo. There was a 2-week washout period between phases, consistent with the short half-life of salsalate (<8 h). Inclusion criteria included normal thyroid, renal, and hepatic function; alcohol intake <28 units/week; no glucocorticoid use in the previous 6 months; no medication, including nonsteroidal anti-inflammatory medication in the previous month or during the study; and no history of dyspepsia or peptic ulcer disease. Local ethical committee approval and written informed consent were obtained."

"...Ten weeks of high-fat feeding caused diet-induced obesity in male C57Bl/6 DIO mice, with elevated fasting plasma insulin levels compared with C57Bl/6 Lean mice (Table 1). On glucose tolerance testing, C57Bl/6 DIO mice were hyperglycemic and hyperinsulinemic compared with C57Bl/6 Lean mice, indicating development of insulin resistance (Table 1 and Fig. 1)."

"...Four weeks of treatment with salicylate (120 mg/kg/day) had little measurable effect in C57Bl/6 Lean mice, except for elevated fasting plasma insulin. In C57Bl/6 DIO mice, salicylate decreased both fasting and postprandial plasma glucose levels (Table 1 and Fig. 1). Furthermore, there was a trend to reduced plasma triglyceride levels after salicylate treatment in C57Bl/6 DIO mice (P = 0.059) (Table 1)."

"...Salicylate significantly reduced 11β-HSD1 mRNA in omental adipose tissue in C57Bl/6 DIO mice, with a similar trend in mesenteric adipose (P = 0.057) (Fig. 2A). In mesenteric adipose of C57Bl/6 DIO mice, salicylate also reduced 11β-HSD1 enzyme activity (Fig. 2B)."

"...Characteristics of the 16 male participants are shown in Table 2. Salicylate levels in plasma averaged 134 ± 33 mg/L during active treatment and were undetectable during placebo. Only 1 of the participants reported tinnitus during salsalate therapy, and there were no changes in indices of insulin sensitivity or lipid profile. Nevertheless, salsalate reduced 11β-HSD1 mRNA levels in subcutaneous adipose, an effect which was unrelated to BMI (Fig. 4) or plasma salicylate levels (data not shown). This was accompanied by reduced transcript levels for MCP-1 (33.6 ± 5.6% suppression, P < 0.02), but not TNF-α or AdiQ. The effect of salsalate on 11β-HSD1 activity appeared restricted to adipose tissue since there was no change in first pass conversion of cortisone to cortisol in liver or in the ratio of cortisol to cortisone metabolites in urine (Fig. 4)."

"...Downregulation of 11β-HSD1 by salicylates is likely to reflect a direct mechanism in adipose tissue, given its replication in an adipocyte cell line. Furthermore, we have demonstrated in vitro that salicylic acid reverses cortisone-mediated suppression of the insulin-sensitizing adipokine AdiQ; since salicylic acid had no effect when the contribution of 11β-HSD1 was negated by removal of steroid or by addition of cortisol, these data indicate that inhibition of 11β-HSD1 by salicylates mediates the altered AdiQ expression also observed in vivo. The downregulation of 11β-HSD1 was selective for the visceral adipose depots in mice but was evident in subcutaneous adipose in humans. Central adipose depots exhibit greater variation in lipolytic activity and more intense proinflammatory responses during high-fat feeding and are more glucocorticoid responsive (49). However, in humans, recent evidence suggests that 11β-HSD1 regenerates more cortisol in subcutaneous than in visceral adipose tissue (50), suggesting species-specific differences. Moreover, we did not find evidence that changes in proinflammatory cytokines, such as TNF-α, mediate the effects of salicylates on 11β-HSD1 expression; the downregulation of TNF-α by salicylates in C57Bl/6 DIO mice, but resistance to this effect in 11β-HSD1KO mice, suggests that effects of salicylates on intra-adipose inflammation may be a consequence rather than cause of downregulation of 11β-HSD1. This is further supported by the downregulation of TNF-α in the visceral adipose of 11β-HSD1KO mice compared with C57Bl/6 mice. In human adipose, TNF-α mRNA did not change in association with altered 11β-HSD1 mRNA. In the absence of cytokine-mediated regulation, more detailed investigation will be required to dissect the molecular mechanisms behind the salicylate-mediated regulation of 11β-HSD1 expression."

"...In conclusion, these findings suggest that the anti-inflammatory agent salsalate alters glucocorticoid metabolism in mice and humans in a pattern that differs between liver and subcutaneous adipose tissue. Downregulation of intra-adipose 11β-HSD1 may contribute to the insulin-sensitizing effect of salicylates."
 

d1d2

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Hi everyone,

Considering the above, could using aspirin cause an increase in eczema or something like ichthyosis vulgaris? I'm curious about a lowered cortisol connection, which by all account seems positive.

I don't normally have eczema problems but have occasionally had ichthyosis. In years past, I've used a hydrocortisone cream that has gotten rid of it. In the last half year, I've increased my twice-daily aspirin dose from a half tablet to about 1 gram. I've noticed skin thickening in one spot on my shins and broader scale-y appearance further down my shin. I used a bit of hydrocortisone cream this time and the thickness reduced. I've stopped using it and just started with halving my aspirin dose in the last day. Based on what you said above, could the reduction in cortisol be what may have allowed emergence of this condition? Cortisol sounds to be immunosuppressive and that's what is said about hydrocortisone and Elidel, I believe. I'll see if it clears up on its own with the lower aspirin amount. A day later with this approach, it doesn't seem as itchy.
 

DaveFoster

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Ray Peat recommends a maximum of 1 g/day of aspirin used indefinitely with 1 mg vitamin K2 per 325 mg aspirin, so 3 mg K2/day minimum.
 

docall18

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Ray Peat recommends a maximum of 1 g/day of aspirin used indefinitely with 1 mg vitamin K2 per 325 mg aspirin, so 3 mg K2/day minimum.

Have you a reference for this?



10/18/12) What is a safe upper limit of aspirin consumption?

Ray Peat said:
It depends on the context; aspirin makes you need more vitamin K, even when you aren't using much. People who use aspirin for arthritis or cancer often take several grams a day.
 

superhuman

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@haidut i know get great benefits from aspirin in terms of reducing my water retention but i still have some, meaning i have high stress. I take 300mg x3 a day but if i increase it i start to get a little ringning in ears etc but this seems mostly from frequency also. Meaning i think half life has to be a bit longer for takibg 3 times a day for me. I feel i could take 1g two times a day, say morning and evening aka 2g daily and not get ringing vs 500mg x3 a day aka 1,5g daily. Can 2 times a day be as good ? And what is the half life? I know some say 4 hours but. Also what can cause ringing?
 

DaveFoster

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Have you a reference for this?



10/18/12) What is a safe upper limit of aspirin consumption?

Ray Peat said:
It depends on the context; aspirin makes you need more vitamin K, even when you aren't using much. People who use aspirin for arthritis or cancer often take several grams a day.
I don't, but it's on the forum. Search "Ray Peat 1 mg K2"
 

DaveFoster

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@haidut i know get great benefits from aspirin in terms of reducing my water retention but i still have some, meaning i have high stress. I take 300mg x3 a day but if i increase it i start to get a little ringning in ears etc but this seems mostly from frequency also. Meaning i think half life has to be a bit longer for takibg 3 times a day for me. I feel i could take 1g two times a day, say morning and evening aka 2g daily and not get ringing vs 500mg x3 a day aka 1,5g daily. Can 2 times a day be as good ? And what is the half life? I know some say 4 hours but. Also what can cause ringing?
Glycine depletion can cause tinnitus (ear-ringing). Try taking every 325 mg aspirin tablet with at 1-2 mg K2 and 2 -3 g glycine.
 
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I think the 1mg per aspirin thing was suggested by a caller or by the radio host, and Ray Peat just said yeah that seems reasonable.
 

DaveFoster

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No, you said ''Ray Peat recommends a maximum of 1 g/day of aspirin'' - have you a reference for this?
He said that high doses can damage your intestines if taken chronically, and he wouldn't take more than 1 gram/day. I don't have the exact quote, but someone could have made up the quote anyway.
 
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