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

Frankdee20

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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

It’s occured on several occasions, I’d pop some Pregnenalone after being riled up, anxious, and it shuts that off, sending me to sleep. This is unpredictable though.
 

doerfast

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It’s occured on several occasions, I’d pop some Pregnenalone after being riled up, anxious, and it shuts that off, sending me to sleep. This is unpredictable though.

So how many mg do you pop? 100? 200? 300? etc.
 
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Frankdee20

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So how many mg do you pop? 100? 200? 300? etc. I've got PTSD and hyperarousal (stuck in the freakin "fight or flight" mode) is the worst part of it so I'm looking for a shutdown of the CRF as the title of this thread states. And no the PTSD isn't from military duty it's from years of ER and ICU. I had an industrial psychologist tell me that PTSD is very prevalent in healthcare workers but that it's swept under the rug due to the fact that if a worker states it his or her career is done with. To get your license renewed you have to swear to a bunch of mental health questions. Also if it was out in the main stream the industry would be scaring off many potential future students. Actually non military PTSD is like 10 times more than military. Healthcare workers, Police, Paramedics, Fireman, abused children, MVA patients etc. all potential PTSD.

Ones childhood experiences play a huge part on one getting PTSD later in life and actually one can get PTSD in childhood. Also 1/3 of the population carry the DRD2 A1 allele gene which means you have 30-40% less dopamine receptors. Dopamine plays a huge part on the stress response as it actually helps one handle stress.

But if this study that is posted on this thread actually does what it states it does it would be HUGE for PTSD and other anxieties. Actually in my book anxiety is anxiety but the shrinks want to label all these different types like PTSD, OCD, SAD, GAD, ADHD, etc. It's all freakin an over active sympathetic nervous system. Nothing else. An over active/stimulated HPA axis.

I'm going to try the 400 mg pregnenolone like the study I posted and take it before bed and see what it does. That study was done by the VA and it showed to work quite well. Keeping my fingers crossed, I should have the 100 mg tablets soon.

I hate Big Pharma with a passion and was told Benzos are one of the hardest drugs to quit so I've never taken them. Might try some beta blocker but I'm going to give this high dose pregnenolone a try. I've taken low doses before but it didn't do a thing for the anxiety and hyperarousal that I could tell.

I’ve never been on high doses, these convert to allopregnenalone. I suppose that’s what elicits antidepressant effects. I’d pop 5, 10 mg at a time, never higher than 20-25 total in a day. These likely go Progesterone pathway.
 

doerfast

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Here is another study using 400 mg pregnenolone. Keeps looking like ole pregnenolone is quite the anxiolytic

The Neurosteroids Allopregnanolone and DHEA Modulate Resting-State Amygdala Connectivity

Conclusion
In summary, allopregnanolone and DHEA reduced amygdala functional connectivity with other regions within amygdala/salience network, and reduced amygdala connectivity with regions of default network in our participants. These findings suggest that neurosteroids modulate amygdala functional connectivity during the resting state, and may shift the balance between salience network and default network at rest. These findings provide insight into the neurocircuitry of anxiety, and suggest that allopregnanolone and DHEA may be potential targets for pharmacological intervention for anxiety psychopathology.
 
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Danny

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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."

How many milligrams dose did they use in this study
 
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haidut

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haidut

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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

I am not surprised it was cancelled as pregnenolone in the right dose would have probably beaten easily the SSRI drugs and gotten pharma majorly pissed. Btw, there is a synthetic pregnenolone version developed for use as an antidepressant and PTSD treatment. The human doses for it are in the 100mg - 150mg daily range, which is what Peat has recommended for pregnenolone in the past.
3β-Methoxypregnenolone - Wikipedia

However, the human studies with depression and bipolar found benefit ONLY for the 30mg - 50mg aily doses and not for higher doses like 200mg. Those studies are posted on the forum so if you search you will find them.
 
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haidut

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This study that you started this thread on. Preg inhibits CRH

Did you read the full post? It talks about concentration and human dosages. It is even underlined and bolded. Not sure how much more explicit I can make it.
 

Danny

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Did you read the full post? It talks about concentration and human dosages. It is even underlined and bolded. Not sure how much more explicit I can make it.
Hey prick Sorry I bothered you
Sorry I f* ckin bothered you.
 

doerfast

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Did you read the full post? It talks about concentration and human dosages. It is even underlined and bolded. Not sure how much more explicit I can make it.

"Not sure how much more explicit I can make it"

Well if you're that stupid then I understand. Otherwise how about answering the question with an answer like "100-150 mg". . Now wouldn't that have been easier than being a smart ****? Duh

Maybe I didn't read the full post or maybe I forgot. Bottom line is your a little f()cking prick
 
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doerfast

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Did you read the full post? It talks about concentration and human dosages. It is even underlined and bolded. Not sure how much more explicit I can make it.

You now another thing haidut I'm going have the FDA do a little surprise visit to your trailer park manufacturing plant you've got going on. Let's see if it's up to snuff with the FDA guidelines and GMP rules. Cause from the looks of things I'm sure they can find a lot of things wrong. The ole FDA loves to send their goons out to supplement companies.

https://www.fda.gov/Food/DietarySupplements/ReportAdverseEvent/
 

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meatbag

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F()ck you. All I asked was the dose in mg not some f() cling prick a$$ response
"Not sure how much more explicit I can make it"

Well if you're that stupid then I understand. Otherwise how about answering the question with an answer like "100-150 mg". . Now wouldn't that have been easier than being a smart ****? Duh

Maybe I didn't read the full post or maybe I forgot. Bottom line is your a little f()cking prick


This is absolutely pathetic and I've reported you. Maybe OP said that because people who can't bother reading basic information or thinking shouldn't be using supplements. From the original post, clearly underlined and in bold to anyone with eyeballs;

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).

I doubt you're familiar but if you press the control key (abbreviated 'Ctrl') while SIMULTANEOUSLY pressing the F key a search box appears and you can type a word or phrase into it and find that on the page your viewing. If you had done this with 'mg' you could have found your answer in 1 second.
 

charlie

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Click. Boom.

iu
 

meatbag

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You now another thing haidut I'm going have the FDA do a little surprise visit to your trailer park manufacturing plant you've got going on. Let's see if it's up to snuff with the FDA guidelines and GMP rules. Cause from the looks of things I'm sure they can find a lot of things wrong. The ole FDA loves to send their goons out to supplement companies.

https://www.fda.gov/Food/DietarySupplements/ReportAdverseEvent/

haidut is a professional and has done important work for several organizations involving biology and chemistry. I think you'd be surprised what happens when you make a claim to law enforcement unnecessarily. These people take their jobs pretty seriously, as they should. Maybe go read the old story the boy who cried wolf.
 
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haidut

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"Not sure how much more explicit I can make it"

Well if you're that stupid then I understand. Otherwise how about answering the question with an answer like "100-150 mg". . Now wouldn't that have been easier than being a smart ****? Duh

Maybe I didn't read the full post or maybe I forgot. Bottom line is your a little f()cking prick

Not sure why you think it is a pricky response. I make the effort to actually post the text from the study, extrapolate the dose needed to achieve this concentration and then underline that part. If nobody takes the time to read what I posted, and relies on asking me question for things that are patently visible at the very beginning of that post then what is the point of a forum??
I do apologize for appearing pricky, written text can be taken out of context. But if you scan through the forum you will see that I say this to many other users when I think the answer has been stated before and easy to find.
 

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