Pregnenolone Is The Most Potent Inhibitor Of The Stress Signal (CRH)

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Braveheart

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Yup... that's us...I have a lot to be grateful for...thank you Blossom!...nice name.
 

Blossom

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Yup... that's us...I have a lot to be grateful for...thank you Blossom!...nice name.
Thank you so much! I'm going to share this information with my dad who is 70 and has the dx of prostate cancer.
 
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Brilliant. To avoid their material from becoming watered-down, some people put the standard "this is for entertainment purposes only" disclaimer on their work, and prefix their advice with "some people have done x" when giving their suggestions to do x.

So the book might be in the pipeline after all? ( and not a figment of my poor metabolism )
 
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TubZy

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Thanks, I am actually getting some of my posts and noted together to write a pratical guidebook on Peatarian substances. I just have to be careful in how much I can say without getting in legal trouble. The substances you mention that protect from aspirin damage are glycine, theanine, caffeine, magnesium, and baking soda. If you search the forum for each of these and aspirin combined you will find the relevant threads.

You should do a book man...
 

kaybb

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Thanks, I am actually getting some of my posts and noted together to write a pratical guidebook on Peatarian substances. I just have to be careful in how much I can say without getting in legal trouble. The substances you mention that protect from aspirin damage are glycine, theanine, caffeine, magnesium, and baking soda. If you search the forum for each of these and aspirin combined you will find the relevant threads.
I need this practical guidebook also!! I'm not good at connecting the dots ...at all! I would pre order!!
 

LeeLemonoil

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I'm always reading up on findings about the pathogenesis(es) of affective disorders.

I've stumbled upon this little abstract
http://www.psyneuen-journal.com/article/S0306-4530(15)00771-4/abstract

some of the authors are very good and knowledegable researchers as far as I can judge.

I'm not aware that the Mineracorticod receptor is given much attention for its role in development of depression. They say here they find it likely that the MR signalling "is attenuated" in depression.

Seems like yet another possible angle to explain positive/anti-depressive effects of substances like Lithium, Natrium and Pregnenolone - all of which may "improve" or modulate pathological MR-signalling?

@Drareg
 

Dante

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I'm always reading up on findings about the pathogenesis(es) of affective disorders.

I've stumbled upon this little abstract
http://www.psyneuen-journal.com/article/S0306-4530(15)00771-4/abstract

some of the authors are very good and knowledegable researchers as far as I can judge.

I'm not aware that the Mineracorticod receptor is given much attention for its role in development of depression. They say here they find it likely that the MR signalling "is attenuated" in depression.

Seems like yet another possible angle to explain positive/anti-depressive effects of substances like Lithium, Natrium and Pregnenolone - all of which may "improve" or modulate pathological MR-signalling?

@Drareg
So, I read up the study, from what i understand is that the depressed patients had "adrenal fatigue" or hpa dysfunction in response to Spiro. I mean for the sake of simplicity , if one assumes cortisol action directly to MR , in healthy patients , it should have left more cortisol in the serum which they detected versus less in depressed patients. So, in this case wouldn't inhibition of primary stress signal be even worse? ( Or have I made some dumb reductionist assumptions here ?)
 

raypeatclips

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Thanks, I am actually getting some of my posts and noted together to write a pratical guidebook on Peatarian substances. I just have to be careful in how much I can say without getting in legal trouble. The substances you mention that protect from aspirin damage are glycine, theanine, caffeine, magnesium, and baking soda. If you search the forum for each of these and aspirin combined you will find the relevant threads.

+1 for this would pay for it.
 

LeeLemonoil

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So, I read up the study, from what i understand is that the depressed patients had "adrenal fatigue" or hpa dysfunction in response to Spiro. I mean for the sake of simplicity , if one assumes cortisol action directly to MR , in healthy patients , it should have left more cortisol in the serum which they detected versus less in depressed patients. So, in this case wouldn't inhibition of primary stress signal be even worse? ( Or have I made some dumb reductionist assumptions here ?)


I have not really understood the design and interpretation either, that's why I posted.
 

Drareg

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I'm always reading up on findings about the pathogenesis(es) of affective disorders.

I've stumbled upon this little abstract
http://www.psyneuen-journal.com/article/S0306-4530(15)00771-4/abstract

some of the authors are very good and knowledegable researchers as far as I can judge.

I'm not aware that the Mineracorticod receptor is given much attention for its role in development of depression. They say here they find it likely that the MR signalling "is attenuated" in depression.

Seems like yet another possible angle to explain positive/anti-depressive effects of substances like Lithium, Natrium and Pregnenolone - all of which may "improve" or modulate pathological MR-signalling?

@Drareg

Speculating on this interesting study-

The age of participants is interesting,40-47, this is the age bracket for a lot of suicides amongst men,we know on here cortisol seems to get a free run in the body at this age as the protective steroids decline,I'm not sure if that means a massive increase of cortisol but more influence as its is not opposed.
It would interesting if we knew the socioeconomic status for speculation.
Also pre spironolactone cortisol levels,was it for example measured or known that high cortisol caused depression or is it self reported depression?

What I'm guessing then is if it's a case of low progesterone in the depressed group and allowing cortisol to cause effect this way,the depressed patients could have benefited slightly from a similar molecule to progesterone because they were initially low so their cortisol does not increase.
However in the healthy bodies if spironolactone is similar to progesterone it's possible the body stopped producing progesterone based on feedback from a similar molecule and allowed cortisol a free run,did the healthy group end up feeling depressed would be interesting to know.
Spironolactone also effects DHT production negatively from what I understand,this would play a role here also I'm guessing .
 

Dante

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Speculating on this interesting study-

The age of participants is interesting,40-47, this is the age bracket for a lot of suicides amongst men,we know on here cortisol seems to get a free run in the body at this age as the protective steroids decline,I'm not sure if that means a massive increase of cortisol but more influence as its is not opposed.
It would interesting if we knew the socioeconomic status for speculation.
Also pre spironolactone cortisol levels,was it for example measured or known that high cortisol caused depression or is it self reported depression?

What I'm guessing then is if it's a case of low progesterone in the depressed group and allowing cortisol to cause effect this way,the depressed patients could have benefited slightly from a similar molecule to progesterone because they were initially low so their cortisol does not increase.
However in the healthy bodies if spironolactone is similar to progesterone it's possible the body stopped producing progesterone based on feedback from a similar molecule and allowed cortisol a free run,did the healthy group end up feeling depressed would be interesting to know.
Spironolactone also effects DHT production negatively from what I understand,this would play a role here also I'm guessing .
The suicide age range thing - is it valid for all regions of the world? The study was conducted in Germany , would this hypothesis be still valid there ?
 

Drareg

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The suicide age range thing - is it valid for all regions of the world? The study was conducted in Germany , would this hypothesis be still valid there ?

Not sure if it's valid for the world but from articles based in the UK ,USA and Europe with anecdotes it seems prevalent at this age,I also heard 20-24 as being quite high,it's hard to get any hard evidence from one source for global rates.
It seems to change too which is probably reflecting economic conditions and much more I'm sure,I'm curious if social media has caused the increase in millennials for example or their easy access to SSRI's and drugs in general.
 

Drareg

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One thing they never report when we hear about a suicide is what cocktail of pills the doctor was given them,this is an issue in the "western"countries imo.
 

ddjd

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Ray recommended to one person over email to combine aspirin and pregnenolone as a potent method to lower cortisol and increase testosterone. I already posted on the ability of aspirin to lower cortisol and increase testosterone on its own, so once again Ray is right on the money


Haidut I've found pregnenolone to be incredibly healing for my panic attacks. They've reduced hugely and I really feel like I'm healing more and more with every dose.

Another intriguing thing was that when I take aspirin a few hours after taking pregnenolone, it somehow makes my hair look better. I very rarely get compliments about my hair, but it's happened 3-4 times now that people have said something about my hair after I've taken this pregnenolone and aspirin combo. Would increased testosterone make my hair look more "alive". Or could it be from the pregnenolone increasing progesterone?
 

Wagner83

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I tried a few times a couple of drops of stressnon before stressful events and it did not help.
 

doerfast

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I think this study should finally put to rest the arguments and debates of whether pregnenolone raises or lowers cortisol, and how it affects the stress response overall. I posted a similar study, which showed that the pregnenolone metabolites progesterone and allopregannolone potently inhibited ACTH release and thus cortisol synthesis.
Pregnenolone Does Not Boost Cortisol, It Lowers It By 60%

CRH (CRF) is the first step in the manifestation of the stress response. It is a hormone produced in the hypothalamus whenever the organism is under stress, and elevations of CRF/CRH signal the pituitary to produce ACTH, and ACTH signals the adrenals to produce cortisol. Elevated levels of CRF/CRH are found in many diseases, especially "mood" disorders like depression, schizophrenia, PTSD, anxiety, etc. It is well-known that the GABA-ergic system in the brain is one of the natural inhibitors of CRH release and this principle is currently applied in using GABA agonist drugs for treating stress conditions and diseases like Cushing that are characterized by high levels of cortisol.
This study looked at the effect of several steroids on the levels of CRF/CRH. The steroids under study included pregnenolone, allopregnanolone, THDOC, DHEA, and the sulfated derivatives pregnenolone sulfate, and dhea sulfate.
It is already well-known that allopregnanolone and THDOC, both being potent GABA agonists, inhbit CRF/CRH release. What the study found surprising was that pregnenolone itself was the most potent inhibitor of CRF/CRH and it has those effects in relatively low concentrations of 1uM - 30uM range. For the purposes of estimating effects in humans, it is brain levels of pregnenolone that would matter given that CRF/CRH is produced in the brain. Brain levels of pregnenolone are on the order of 100-fold higher than serum levels. I posted a human study in the Pansterone thread showing that a single oral dose of 175mg pregnenolone produced serum levels of 0.5uM in humans and it kept those levels for up to 24 hours. This suggests that the 175mg dose produced brain concentrations of about 50uM. So, to achieve the 30uM concentration found to be most effective for lowering CRF/CRH in the study, one would need about 100mg pregnolone (assuming linear scaling). As many of you here know, Ray has consistently recommended 100mg - 150mg of pregnenolone as a good dose for inhibiting stress, and improving overall health. Given the almost complete absense of studies on pregnenolone bioavailability and pharmacokinetics in humans, the ability of Ray to predict proper dosages of these substances (often decades in advance) is simply astounding!!
One last thing of note is that the steroid allopregnanolone investigated in the study as well is a metabolite of pregnenolone through the progesterone pathways and the activity of the enzyme 5-AR. The scientists suspected that pregnenolone may be inhibiting CRF/CRH through its conversion into allopregnanolone, so they also used the drug finasteride in combination with pregnenolone in order to block its conversion into allopreganolone. Pregnenolone still has the same strong inhibitory effect on CRF/CRH, which means its anti-stress action is intrinsic. That being said, by converting into allopregnanolone as well, pregnenolone may have double anti-stress action - once as an intrinsic effect of pregnenolone, and a second one through the GABA-ergic system activated by its metabolite allopreganolone.
So, pregnenolone is accumulating more and more evidence as one of the primary tools for lowering stress and improving overall health, especially in the brain. Ray recommended to one person over email to combine aspirin and pregnenolone as a potent method to lower cortisol and increase testosterone. I already posted on the ability of aspirin to lower cortisol and increase testosterone on its own, so once again Ray is right on the money.
Aspirin Decreases Cortisol And Increases Testosterone In Humans

Finally, the stress-inhibiting effect of pregnenolone, combined with its ability to raise metabolism, and lower estrogen/cortisol, make it a prime candidate for treating not only mental conditions but also the so-called metabolic syndrome and especially obesity. Both of the latter are conditions almost entirely driven by the CRF/CRH-ACTH-cortisol-estrogen cascade.
Pregnenolone For Obesity And Insulin Resistance
How Pregnenolone And Progesterone Raise Metabolism
Pregnenolone (should) lower estrogen levels

OK, enough of my rant:) Here is the actual study.

Effects of neurosteroids on the human corticotropin-releasing hormone gene. - PubMed - NCBI
"...Corticotropin-releasing hormone (CRH), a peptide synthesized mainly in the paraventricular nuclei (PVN) of the hypothalamus, is a key regulator of hypothalamic-pituitary-adrenal (HPA) axis activity during stress. CRH via pituitary adrenocorticotropic hormone (ACTH) stimulates glucocorticoid synthesis and release from adrenal glands. In turn, glucocorticoids inhibit production of CRH in PVN and ACTH in pituitary by a feedback mechanism. CRH hypersecretion in the central nervous system (CNS) is thought to be an important factor in pathogenesis of some stress-related diseases, such as major depressive disorders, post-traumatic stress disorder (PTSD) or panic disorder [34, 39, 42, 55]. The elevated CRH concentrations in the cerebrospinal fluid and the increased number of CRH-expressing neurons in the hypothalamus have been found in depressed patients [29, 37]. Similarly, the increased CRH concentration or dysregulation of cortisol secretion has been observed in patients with PTSD and panic disorders [11,42]. Also in experimental animals, central administration of CRH or overproduction of this peptide in transgenic mice evoked anxiety, depression, and schizophrenia-like behavior [3, 12, 47]. A large number of preclinical studies have indicated that anxiety-like behavior results from the action of CRH through CRH1 receptor."

"...Apart from CRH1 receptor blockade, another possibility of limiting CRH effect could involve repression of the synthesis of this peptide. Interestingly, although CRH synthesis is augmented by many neurotransmitters and neuropeptides, only two major mechanisms are known to inhibit the HPA axis activity, namely the glucocorticoid negative feedback and the gaminobutyric acid (GABA) [17]. Among compounds acting on GABA receptors, neurosteroids deserve the special attention. Neurosteroids are precursors or metabolites of steroid hormones, which do not show affinities for intracellular steroid hormone receptors, but modulate the action of some membrane receptors, such as GABA, NMDA and sigma-1 [24, 45]. Steroid metabolites with hydroxyl group in the position 3 and with reduced ring A, i.e., allopregnanolone (3a-hydroxy-5a-pregnan20-one, ALLO) and allotetrahydrodeoxycorticosterone (THDOC) are among the most potent allosteric positive modulators of the GABA receptors and exert anxiolytic and antiepileptic activity [7, 9]. Concentrations of ALLO and THDOC are increased in plasma and CNS in response to acute stress and that leads to effect HPA axis activity [14, 36]. Moreover, ALLO and THDOC attenuate the anxiogenic activity of CRH and the methoxamine-stimulated CRH release [33]. Contrary to acute stress, chronic stress decreases brain ALLO concentration and disturbs negative feedback mechanism of HPA regulation."

"...The excitatory neurosteroid, PGL [pregnenolone] potently and in a concentration-dependent manner (0.3–30 μM) inhibited CRH-CAT activity, whereas its sulfate form was active only at high (30 μM) concentration (Fig. 2A and 2B). Similarly as basal activity, also forskolin-stimulated gene transcription was potently inhibited by PGL (1–30 μM), while PGL-S was inactive in these concentrations (Fig. 2C and 2B)."

"...The 5a-reductase inhibitor – finasteride, at 0.1 and 1 μM did not change the basal CAT activity and had no effect on PGL (1 μM) inhibition of CRH gene promoter activity (Fig. 5)."

"...In the present study, we found that some neurosteroids in a concentration-dependent manner inhibited CRH gene promoter activity in the differentiated Neuro-2A cells. Among investigated neurosteroids, PGL [pregnenolone], the main precursor of steroid hormones, exerted the most potent effect. ALLO and THDOC, two potent endogenous positive modulators of the GABA receptors had only a little weaker inhibitory effect than PGL on CRH activity. It is likely that the inhibitory effect of ALLO and THDOC on CRH gene transcription may be implicated in the mechanism of their anxiolytic action."


Looks like the VA was going to do a study using pregnenolone for PTSD but their funding was turned down:

Adjunctive Pregnenolone in Post-Traumatic Stress Disorder (PTSD) and Depression in Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) Veterans - Full Text View - ClinicalTrials.gov

Adjunctive Pregnenolone in Post-Traumatic Stress Disorder (PTSD) and Depression in Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) Veterans
This study has been withdrawn prior to enrollment.
(PI turned down funding.)
Sponsor:
VA Office of Research and Development
ClinicalTrials.gov Identifier:
NCT00993629
First Posted: October 12, 2009
Last Update Posted: October 27, 2014
 

doerfast

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Looks like the VA was going to do a study using pregnenolone for PTSD but their funding was turned down:

Adjunctive Pregnenolone in Post-Traumatic Stress Disorder (PTSD) and Depression in Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) Veterans - Full Text View - ClinicalTrials.gov

Adjunctive Pregnenolone in Post-Traumatic Stress Disorder (PTSD) and Depression in Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) Veterans
This study has been withdrawn prior to enrollment.
(PI turned down funding.)
Sponsor:
VA Office of Research and Development
ClinicalTrials.gov Identifier:
NCT00993629
First Posted: October 12, 2009
Last Update Posted: October 27, 2014


THEY WERE USING 400 mg ORAL Pregnenolone IN THIS STUDY:

Allopregnanolone Elevations Following Pregnenolone Administration are Associated with Enhanced Activation of Emotion Regulation Neurocircuits



In conclusion, we demonstrate that pregnenolone administration (leading to increased downstream allopregnanolone levels) reduces activity in regions associated with the generation of negative emotion and enhances activity in regions linked to regulatory control over emotion, as well as increasing connectivity between two of these regions (dmPFC and amygdala). Considering the wealth of evidence that neurocircuits involving these regions are altered in anxiety disorders, our results invite further investigation into the brain basis for allopregnanolone’s use as an anxiolytic pharmacological intervention.
 
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Frankdee20

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Dosage truly matters here, It’s been stated before how low doses (5-30mg) are less likely to convert to allopregnenalone. I take anywhere from 5-15-20 mg a day, and it’s mostly a stress response queller, slash sedative, great sleep enhancer. I would never call it an antidepressant at these doses. It’s not even a cognitive enhancer, but it dulls me out, so I take in evening, before bed. I’m sure 50-100 mg produce different effects.
 

doerfast

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Has anyone used high dose (100 mg + ) of pregnenolone for blocking the stress response, as in anxiety, and it ACTUALLY worked for them and if so how long did it take to see results? Thanks
 

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