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Mifepristone for Depression & HPA axis Dysfunction

hpa axis mifepristone

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#31 Flex

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Posted 02 October 2014 - 10:59 AM

No its perscription only and in addition the German customs are problematic.

Couldnt You order form a Canadian pharmacy ?

 

 



#32 binder23

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Posted 05 October 2014 - 01:03 AM

Hi All. I think this protocol holds a lot of potential - this thread got me to officially join Longecity.  :)

 

I'm sorry if this is presumptuous as a first post, but I do have few questions.

 

1. Unless I'm reading the cited study incorrectly, the dosage and administration was described as "Mifepristone (50 mg/kg body weight; Sigma, St Louis, MO, USA) was dissolved in 15 µL ethanol/1.5 mL coffee cream (Campina, Woerden, The Netherlands)" and administered orally.  The study was done in rats, but for someone like myself who weighs 185 pounds, this would equate to a 4200mg dose? Am I missing something?

 

2.  Some posters have mentioned some other studies that are out there (Joe thank you for sharing your interest and knowledge in this area :)). I was wondering other regimens/protocols have been studied, I know someone mentioned an 800mg dosage.  Would anyone be able to provide links to some of these studies?

 

Thanks in advance. I really think this could be a pretty significant breakthrough.

 

 

 

 



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#33 computeTHIS

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Posted 05 October 2014 - 07:35 AM

Interesting to hear your report. What made you space the doses apart that way?

 

I was differentiating from placebo effect.  The claims from the Plos One article, based on a single dose, seemed rather incredible.  Positive effects in other articles were reported at the 200mg dose, so I didn't bother messing with that either, given that I'm fairly below-average for my weight anyways.  I definitely notice positive effects from a single dose, regardless of spacing.

 

As I mentioned to someone else, I'm rather sensitive to stimulants such as coffee.  If I have a bit too much coffee, I feel totally knocked out the next day.  I've been careful to drink it sparingly, 1 cup at most in a day.  About 3 weeks ago, I had a bit too much coffee (2-3 cups in a day), and the next day I felt totally drained of energy.  I decided to take another 200mg dose of Mifepristone (my 6th now), and without thinking about it I also had a cup of coffee at the time.  I was able to rapidly recover my energy following coffee cessation.  About 2 weeks later, I had a large cup of coffee, which seemed to have none of the usual effects of coffee or caffeine (jitteryness, hypertensive-feeling, etc).  It would seem to me that Mifepristone has very strong, long-lasting effects on cortisol regulation, given my experience with its inhibitory effects on caffeine.  I would recommend to anyone else seeking recovery from fatigue to cut out, or cut down stimulants, as part of a therapeutic regimine correcting cortisol levels.  Although normally, without Mifepristone I would still have been indefinitely bed-ridden in the absence caffeine, in my experience. 

I'm still doing quite well, but I don't see Mifepristone as the cure-all for my fatigue.  Other hormones seemed to remain out of balance, testosterone, for example.  Thinking of the pituitary as my primary therapeutic target, my readings brought me to some other chemicals: CJC-1295 (with DAC), GHRP-6, and single-dose Triptorelin, things which bodybuilders seem to use for steroid recovery, and as it happens, the supressive effects of their steroid use may have some commonalities with stress-induced chronic fatigue.  I've tried each of these in sequence, and in combination (as documentation recommends) and have had very positive results, but it's only been 1 week, so I'll report more later on those (and link you to another thread on it).  Along those lines though, I think a healthy IGF1 level is necessary for neurogenesis, particularly if you're trying to recover something like pituitary function. 


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#34 Flex

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Posted 05 October 2014 - 01:36 PM

@ binder23

No it wouldnt equate to 4200mg, because there is a Animal human equitation.

.. mg/kg x (6/37)

 

185 pounds / 2 = 92.5 Kg

50mg/kg x (6/37) = 8.11 x 92.5 = 750mg

 

Consider possible side-effects, if 200mg are sufficient and 750mg exceed the recommened dosage,

then better avoid any risks.

 

@ Compute this

 

IGF-1 reduces GR at least in the peripehral tissue 

Modulation of glucocorticoid metabolism by the growth hormone - IGF-1 axis.

http://www.ncbi.nlm....pubmed/17371460

 

For more infos, see the link of my similair thread on post #27

Btw: IIRC according to one of the last posted links in my thread, high Glucocoricoids levels arent allways measurable


Edited by Flex, 05 October 2014 - 01:38 PM.


#35 totflare

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Posted 05 October 2014 - 03:04 PM

I've been interested in Mifepristone for some time. It's too damn bad it's hard to get because I would love to try it.

 

After some research I've done blood pressure medicine like candesartan might also have potential for HPA axis modulation.

 

A centrally acting, anxiolytic angiotensin II AT1 receptor antagonist prevents the isolation stress-induced decrease in cortical CRF1 receptor and benzodiazepine binding. http://www.ncbi.nlm....pubmed/16205776  

#36 Flex

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Posted 05 October 2014 - 05:12 PM

Interrestingly Mifepristone seems to decrease cortisol but increase the "cortisol releaser" ACTH

http://www.hindawi.c...12/393251/tab1/

http://www.hindawi.c...rt/2012/393251/

 

But possibly have some toxic effects to photoreceptors

http://www.iovs.org/.../1/313.full.pdf

 

I guess that would be a reason to avoid any high dosage


Edited by Flex, 05 October 2014 - 05:14 PM.


#37 binder23

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Posted 06 October 2014 - 02:00 AM

Thanks for the info Flex. This article about a study of Mifepristone on Cushing's (High ACTH high Cortisol) patients says that mifepristone blocks the effects of cortisol at the tissue level without a reduction in serum cortisol:

 

http://www.medscape....warticle/823447

 

I'm more interested in this application personally. I have significant HPA dysregulation that I believe was brought on by a medication-induced acute Cushinoid-ish state. I've  also found an online supplier that doesn't require a prescription with good references. - pills around $33 if you buy 12.

 

PTSD presents a blunted ACTH response to CRF with lowered 24-hour cortisol levels from what I've read, so it seems that Mifeprestone can have differential ameliorative effects depending on the underlying type of HPA dysfunction.


Edited by binder23, 06 October 2014 - 02:11 AM.


#38 Flex

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Posted 07 October 2014 - 03:37 PM

Thank You too.
I didnt know this from Mifepristone.
 
By tipping "mineralocorticoid mesolimbic dopamine" in google I´ve got those results:

It has been suggested that elevated geriatric depressive symptoms in val carriers
may be the result of depressive symptoms in val carriers may be the result of lifelong exposure to elevated cortisol
(Kuningas et al. 2007).
This interpretation is consonant with sensitization (‘kindling’)processes, whereby repeated stressors and depressive episodes lead to changes leaving individuals susceptible or ‘kindled’
to develop later depressive episodes independent of stress(Kendler et al. 2000; Post 1992)
The impact of mineralocorticoid receptor ISO/VAL genotype (rs5522) and stress on reward learning
http://bogdanlab.com...ogdan_GBB10.pdf

http://books.google....opamine&f=false

http://www.ncbi.nlm..../pubmed/9879980
http://www.ncbi.nlm..../pubmed/1656321
http://www.ncbi.nlm....les/PMC2941442/

So it seems to me that MR Receptor activation, by MR´s or GR´s, can lead to deppresive symptoms via decrasing Dopamine transmission in the Mesolimbic system and that Drugs can make one more sensitive to this.
I think thats what happened to me
Because Coffee, Adrenaline an Potassium activation/release are all linked to GR/MR activation.

Dont know whether I´ve mentioned it but Cortisol increases 11betaHSD-1 mRna, so by inhibiting it with e.g. Mifepristone, the cycle should break
 
 
Edit: or the other way arround :dry:

The impact of mineralocorticoid receptor ISO/VAL genotype (rs5522) and stress on reward learning
The mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) regulate the onset and termination,

respectively, of the hypothalamic–pituitary–adrenal (HPA) axis stress response (Joelset al. 2008).

Antidepressant medica-tions increase MR expression (DeRijk et al. 2008),

which is associated with reduced depressive- and anxiety-like behavior as well as reduced corticosterone levels during stressfuland basal conditions (Mitraet al. 2009; Rozeboom et al.2007).

 

Conversely, chronic stress results in reduced MR expression (Sterlemann et al. 2008) and MR antagonists
increase basal and stress-induced cortisol levels and worsen antidepressant response

(Arvat et al. 2001; Pace & Spencer 2005; Wellhoener et al. 2004)

 

In this case would, beside Mifepristone, Mullberry bark extract, Propolis and perhaps Dan Shen help.

for more infos read my thread in post #27


Edited by Flex, 07 October 2014 - 03:57 PM.


#39 binder23

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Posted 07 October 2014 - 10:29 PM

Flex,

 

That's super interesting.

 

Do you know if Dan Shen has stronger antagonistic effect on GR or MR? Or are the effects similar on both the glucocorticoid and mineralocorticoid systems ? I ask because I don't see mineralocorticoids as being a problem with me - my sodium and potassium levels are normal. Yet I display all the symptoms of hyercortisolism (or, more accurately, corticoid sensitivity).

 

I have some Dan Shen that I will try today as I'm waiting for the Mifeprestone to arrive.

 

 

Thanks

 


Edited by binder23, 07 October 2014 - 10:31 PM.


#40 Kompota

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Posted 08 October 2014 - 01:35 PM

I just read that Mifepristone binds to the GR with fourfold (!!!) higher affinity than Dexamethasone, which is being considered the heavy artillery of steroid medication. That is impressive.

That would perhaps mean that:

- It should work pretty much immediately, right from the start without building up momentum

- Combined with it's long half-life, lower dosages might be sufficient for a noticeable effect or dosages may be spread out. That would mean lower cost, although the pill by itself is very expensive.  



#41 Flex

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Posted 08 October 2014 - 05:26 PM

You mean expensive on the longterm ?



#42 YoungSchizo

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Posted 08 October 2014 - 05:57 PM

Group-buy possibilities?



#43 Flex

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Posted 08 October 2014 - 06:51 PM

I dont need a hughe ammount, but a few pills.

But if I dont find a source, I would probably be in.



#44 binder23

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Posted 08 October 2014 - 08:57 PM

I bought 6 from a supplier with good references. If the package arrives ok and the product is the correct type, I will be happy to share the source with you. This is a good reference to help in determining if a pill is genuine:

 

http://www.womenonwa...egyne-look-like

 

What do you think is a good regimen? If anyone has any suggestions I'm open to hearing them. I was planning on taking 800mg for the first dose and the remaining 400mg perhaps two weeks later. If that doesn't achieve the desired effect, I may attempt something like 200-400mg every four days.

 

From what I've read, I don't think that Mifeprestone would be necessary to take long term, except perhaps in endogenous Cushing's where your adrenals are producing unnaturally high levels of corticoids continuously (due to physical hyperplastic malformation of the adrenals and/or brain tumors, something distinct from simple HPA dysregulation).


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#45 Anewlife

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Posted 09 October 2014 - 07:55 AM

Hmmm messing with cortisol is dangerous isn't it?

So this drug did or didn't get fda papproval? I followed up on cerobrolysin here and it seems sketchy.

Lol at following what bodybuilders do.

Sorry just playing devils advocate.

#46 lourdaud

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Posted 09 October 2014 - 03:04 PM

Hmmm messing with cortisol is dangerous isn't it?

So this drug did or didn't get fda papproval? I followed up on cerobrolysin here and it seems sketchy.

Lol at following what bodybuilders do.

Sorry just playing devils advocate.

 

Yeah, I'm curious: what if you take this and your cortisol levels are already low, no risk for complications? 



#47 binder23

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Posted 09 October 2014 - 06:42 PM

Hi Anewlife,

 

The drug has gotten FDA approval for endogenous Cushing's (http://www.korlym.com) and of course for abortion. There were several drug trial studies that were conducted for other applications (such as psychotic depression) that were canceled with no information made available that I can find.

 

There are known human side effects from chronic mifepristone administration (http://www.ncbi.nlm....les/PMC2671735/), although they appear to be milder at lower doses and abate after discontinuation. Luckily, I don't think anyone I've seen posting here is considering long term administration, and the availability and price of mifepristone are substantially prohibitive to allowing most of us in a first-world country to do so without a prescription.

 

A study I've seen that does trouble me is this one: http://www.iovs.org/.../1/313.full.pdf in which mifepristone administration was found to cause photoreceptor death independent of dose in two species of mice. The authors acknowledge at the end of the article that no visual abnormalities were reported in human trials of mifepristone, but perhaps those operating the studies were not looking for such sides effect.

 

I think most of us are more interested in applications such as this: http://www.plosone.o...al.pone.0046224. If one or two administrations are enough to re-regulate HPA function with a small risk of short term side effects, I think many would consider that worth a try.

 

@lourdaud

 

I don't know, although Mifepristone raised ACTH and Cortisol levels in study subjects with PTSD: http://www.hindawi.c...12/393251/tab1/

 

It seems the drug produces different effects depending on the underlying HPA dysfunction.

 

Also, this is just my opinion, I think too much emphasis is placed  on cortisol levels at a point in time or over 24-hour period. Unless someone has genuine Cushing's or Addison's disease, designations of hyper or hypocortisolism, I think, are not of much value. For instance, PTSD patients exhibit generally diminished ACTH and Cortisol levels over 24 hours, but when exposed to stressful stimuli these levels increase drastically. Abnormalities in neuroplasticity (hippocampal and pituitary) and subsequent HPA dysregulation are the likely cause of PTSD, not serum cortisol or catecholamine levels, or even the plasticity of the adrenal glands themselves (although this is a loaded statement as nearly everything in pathology is inextricably interrelated).

 

 

 



#48 Flex

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Posted 09 October 2014 - 07:56 PM

I would be interrested in any source within the EU.

Could please anyone tell me one or PM ?

 



#49 totflare

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Posted 09 October 2014 - 08:37 PM

I'm also interested in a legit source in Europe.



#50 YoungSchizo

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Posted 09 October 2014 - 10:02 PM

count me in too



#51 Flex

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Posted 10 October 2014 - 05:53 PM

I´ve sent a request to someone within the EU.

I´ll keep You updated.


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#52 Anewlife

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Posted 10 October 2014 - 07:43 PM

Good luck guys. I'm passing on this for now. Need to be good for my shrink anyhow.

#53 binder23

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Posted 10 October 2014 - 10:50 PM

I received 8 pills in the mail today. I will report on the results.

 

I'm in the US and (surprisingly) found a domestic supplier. Hopefully they won't get shut down anytime soon.



#54 StevesPetRat

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Posted 10 October 2014 - 11:08 PM

I believe firmly that my chronic fatigue was due to chronic, uncontrolled stress, so I maintain low stress levels now as well.  I suspect I permanently down-regulated my IGF1 levels through intermittent fasting when I was young as well.  I weigh now 140 lbs, and the fatigue particularly contributed to wasting and atrophy. 
Based on my labs my pituitary is working, just at a very low level.  I think I'll try CJC-1295 as well, in one study it restored rat pituitary to normal size in Br-M3-KO mice:
 

Neuronal M3 muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth.
Abstract

This is a fascinating thread, I'm marking this study in particular for later reference. Thanks for posting everyone. It cheers me up (? maybe not quite the right phrase...) to see so many people have similar problems to mine. It's also frustrating to note how woefully inadequate conventional treatments are.

#55 Flex

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Posted 11 October 2014 - 01:06 AM

IIRC in one of the Studies/Abstracts above, its mentioned that certain antidepressants do increase MR receptor expression.

So if anybody isnt able to recieve it this could be a alternative, although not as good as Mifepristone.



#56 Flex

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Posted 13 October 2014 - 03:35 PM

I´ve sent a request to someone within the EU.

I´ll keep You updated.

 

The response came and they said that they arent able to obtain it.

I´ve sent the next request to http://www.qhi.co.uk

Will keep You updated.


Edited by Flex, 13 October 2014 - 04:17 PM.

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#57 Joe Monroe

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Posted 14 October 2014 - 02:16 AM

I received 8 pills in the mail today. I will report on the results.

 

I'm in the US and (surprisingly) found a domestic supplier. Hopefully they won't get shut down anytime soon.

Wow that's great! sounds really promising, I live in the usa so definitely let us know how it goes 

 

Also great posts everyone, really liking the discussion. Seeing as how people use it regularly for cushings I coudlnt' see it being that bad, and it also seems that there's very little side effects too. 

 

I'm not sure about the phororecepotor damage, I mean in humans there has been no visual evidence. Sometimes certain things only occur in a certain species. Like I remember reading about high doses of ketamine and other dissociatives could cause... this one disease I forget the name but it was only evident in rodents. 


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#58 Flex

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Posted 14 October 2014 - 03:27 PM

 

I´ve sent a request to someone within the EU.

I´ll keep You updated.

 

The response came and they said that they arent able to obtain it.

I´ve sent the next request to http://www.qhi.co.uk

Will keep You updated.

 

 

Got also the response that they cant get it -.-


Edited by Flex, 14 October 2014 - 03:28 PM.


#59 totflare

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Posted 14 October 2014 - 04:23 PM

15,16-Dihydrotanshinone I extract of Danshen is a potent MR/GR antagonist. Don't know how much of it there is in a whole herb powder of Danshen. 15,16-Dihydrotanshinone I can be found in a supplement called Lean Xtreme but it's together with other substances. 

 

The only place to get pure 15,16-Dihydrotanshinone I that I know of is here:

 

http://www.sigmaaldr...uct/sigma/d0947


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#60 Flex

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Posted 14 October 2014 - 05:38 PM

It seems that Salvia has a modulating effect.

The first time the Pain came back after a few days, and this went on and off

but now it seems to have gone.

 

I have somehow the feeling that when having anxiety or high negative stress, the pain will reactivate.

My source was this half-extract half-powder

http://acugrapheurop...-shen-100g.html

 

If You want to be on the saferside: buy Your self Vitamine K1 drops with 20mg/ml Vitamin K.

Just ask for an anticoagulant antidote and dont mix the Dan-Shen with Aspirine, Tumeric & etc.  

 

I´m curious how Dan-Shen is comparable with Mifepristone and would still try it.

If somebody order it from the site posted by binder23, would You buy me one too and redirect it to me ?


Edited by Flex, 14 October 2014 - 05:44 PM.





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