Allopregnanolone pill -- coming in 6-7 years

[dannyfc]

TSPO represents the starting point and an important rate-limiting step in neurosteroidogenesis. It gives access to neurosteroids in the brain by regulating the entry of cholesterol into the inner mitochondrial membranes and its conversion to pregnenolone by P450scc, which is located in the inner mitochondrial membrane (29; 114). A cascade of enzymatic processes then take place in the cytosol, resulting in the production of neuroactive steroids, including pregnenolone sulfate, DHEAS (though apparently not in human brain (115)], THDOC, and allopregnanolone (reviewed in 31). New molecules that bind with high affinity to TSPO have been recently investigated. These drugs are able to exert important anxiolytic effects but are devoid of the unwanted side effects associated with benzodiazepines, including over-sedation and tolerance (28; 29).

In mouse models, TSPO agents have been shown to potently increase pregnenolone levels in the hippocampus and cortex, as well as to induce anxiolytic effects (116-119). TSPO ligands include XBD173 and etifoxine, which have proven to be highly efficacious anxiolytic and antidepressant drugs in a number of behavioral tests (29; 30). The anxiolytic and antidepressant effects of these agents were related their ability to increase neurosteroid biosynthesis, as confirmed by studies in which key enzyme blockers for neurosteroid biosynthesis, including finasteride and trilostane (56; 30), were used. TSPO ligands have recently showed promising therapeutic effects in clinical studies

TSPO controls conversion of cholesterol, progesterone etc. to allopregnanolone. Finasteride blocks this biosynthesis.

Would this explain why both my cholesterol & progesterone are above lab ranges?

Got some Glycine. Gunna get some etifoxine. Will see how it goes.

[xptriado]

i would say ANYTHING is possible… bloody poison was given to us…

I just ordered Gelsemium Sempervirens 5CH like in the study I posted. It will arrive tomorrow to my pharmacy. I couldn’t get the bloody glycine ANYWHERE. I have to get it in Amazon. There was a place I could buy it but the brand was S*lgar and I read this brand is not very good anymore…

Where did you get your glycine? Try 1-3g like in the study, at night.

Please please please wuold you let us all know how it made you feel?

I will do the same for Gelsemium

[xptriado]

amazon has some very good reviews on glycine…people say it helped them sleep when ambien didnt even work

[MentalNorman]

xptriado, I am from united states. I usually get my supplements locally or from iherb.com. Yes, now is generally a good brand. I usually get now,solgar, or gnc.

[xptriado]

so maybe that means i can get Solgar glycine? Is solgar good? I have read not so good things about it…

I also found this blend I want to try: amazon.de/gp/product/B0006U6 … ZUFJTO5MR1

And I wanted to try Seriphos as well as Sublingual Melatonin when I wake up early at night…

Have you tried any of these?

[MentalNorman]

I always assumed solgar was ok but NOW seemes to get higher scores overall. What negative things have you read about Solgar? Actually you could get NOW Glycine if you wanted. That’s on Iherb as well 1000 mg

iherb.com/Now-Foods-Glycine- … =null&ic=4. When I purchase Glycine I’ll probably get that one.

yes. I’ve been taking sublingual Melatonin the last couple weeks actually. I take 2 10 mg tablets before I lay down to sleep, usually takes about an hour to kick in so i’m probably going to start taking them a bit earlier.

wikihow.com/Take-Melatonin - this Melatonin write up says you should only take melatonin before you initially go to sleep and not in the middle of the night.

[dannyfc]

Why hasn’t etifoxine been previously discussed? Progesterone has been talked about extensively, but if the mechanism of conversion is impaired, it’s going about the problem a backward way. I don’t know if etifoxine can reverse the damage done, but it’s surely worth trying? I’ll have some arrive next week.

A disordered regulation of neuroactive steroids release in response to acute stress could induce GABAergic dysfunctions underlying anxiety disorders.

First, we conducted studies indicating that a short immobilization stress in anxious Balb/cByJ mice produced an anticonvulsive effect. Second, the effects of different positive allosteric modulators (etifoxine, progesterone, clonazepam, and allopregnanolone) of GABAA receptors were compared in a mouse model mimicking the disruption of the acute stress-induced neuroactive steroids release with finasteride (types I and II 5α-reductase inhibitor).

Effects of etifoxine (EFX; mg/kg) (a), of progesterone (PROG; mg/kg) (b), of clonazepam (CLON; μg/kg) ©, and of allopregnanolone (ALLO; mg/kg) (d) on the finasteride (FINA; mg/kg)-induced lowering in clonic seizure threshold for TBPS infusion in stressed mice.

At the highest dose tested (50 mg/kg; Fig. 4 a), etifoxine prevented the finasteride-induced lowering in the threshold dose whereas the 25 mg/kg dose was ineffective.

Unlike etifoxine, progesterone, up to the 30 mg/kg dose (the highest dose devoid of intrinsic activity relative to the control), failed to reverse the finasteride effect (Fig. 4 b).

The lowering of threshold dose induced by finasteride was significantly reversed by allopregnanolone at the 10 mg/kg dose, which was a subactive dose in the stressed animals (Fig. 4 d).

These findings support the hypothesis suggesting an involvement of neuroactive steroids in the anticonvulsive effect of restraint stress. The dual and complementary mechanisms of action of etifoxine (directly on the GABAA receptor and indirectly via the neuroactive steroids) may represent a therapeutic benefit in the treatment of various anxiety disorders with abnormal production of neuroactive steroids.

Peripheral benzodiazepine receptors (PBR) might be involved in certain pathophysiological events, such as anxiety, by stimulating the production of neuroactive steroids in the brain. A recent electrophysiological study has revealed an interaction between PK11195, a PBR ligand and the anxiolytic compound etifoxine at micromolar concentrations. The present work was aimed at further characterizing the etifoxine-PBR interaction. In membrane preparations from intact male rat forebrain, etifoxine uncompetitively inhibited the binding of [(3)H]PK11195 with an IC(50)=18.3+/-1.2 muM, a value consistent with etifoxine plasma and brain concentrations measured after an anxiolytic-like dose (50 mg/kg). In vivo, that etifoxine dose was associated with increased concentrations of pregnenolone, progesterone, 5alpha-dihydroprogesterone and allopregnanolone in plasma and brain of sham-operated animals. In adrenalectomized and castrated rats, etifoxine enhanced the brain levels of these steroids, suggesting a stimulation of their local synthesis and/or a decrease of their disappearance rate, independently of peripheral sources. Finasteride, an inhibitor of 5alpha-reductase that converts progesterone into its 5alpha-reduced metabolites like allopregnanolone, attenuated the anti-conflict effect of etifoxine even though brain allopregnanolone contents were drastically reduced. These results indicate that following activation of the PBR in the brain, an increased cerebral production of allopregnanolone, a potent positive modulator of the GABA(A) receptor function, may partially contribute to the anxiolytic-like effects of etifoxine.

Hyperactivity of the corticotropin-releasing factor (CRF) system occurs in some patients with anxiety disorders and depression. Blockade of CRF1 and CRF2 receptors can underlie the anxiolytic effects of drugs. In the present investigation, in vivo and in vitro studies were designed to determine whether the anxiolytic drug etifoxine, known to enhance GABAergic synaptic transmission, behaves also as a CRF1 and CRF2 receptor antagonist. A drug exerting multiple actions may be of clinical interest in the treatment of various different forms of mood disorders. Using two animal models, it was found that etifoxine reversed the excess CRF-induced grooming but not the hypo-locomotion of the rat placed in an open field. Etifoxine attenuated the CRF-induced gastric emptying delay in the mouse. On the other hand, in vitro, binding of etifoxine to CRF1 and CRF2 receptors on rat brain membranes was negligible and functionally, etifoxine did not block the CRF1 and CRF2 activation-induced cAMP production in presence of CRF in human neuroblastoma SH-SY5Y cells. The selective anxiolytic properties of etifoxine appear unrelated to an antagonist activity at the CRF1 and CRF2 receptors. The decrease in CRF activity produced by etifoxine may be related to its GABAergic properties

Etifoxine (6-chloro-2-ethylamino-4-methyl-4-phenyl-4H-3,1-benzoxazine hydrochloride), a nonbenzodiazepine anxiolytic drug, potentiates GABA(A) receptor function perhaps through stimulation of neurosteroid biosynthesis. However, the exact mechanism of etifoxine action is not fully understood. In this study, we have assessed the possible role of GABAergic neurosteroid like allopregnanolone (ALLO) in the anxiolytic-like effect of etifoxine in rats using elevated plus maze test. Selective GABA(A) receptor agonist, muscimol, ALLO or neurosteroidogenic agents like progesterone, metyrapone or mitochondrial diazepam binding inhibitor receptor (MDR) agonist, FGIN 1-27 significantly heightened the etifoxine-induced anxiolysis. On the other hand, GABA(A) receptor antagonist, bicuculline or neurosteroid biosynthesis inhibitors like finasteride, indomethacin, trilostane or PBR antagonist, PK11195 significantly blocked the effect of etifoxine. Bilateral adrenalectomy did not influence anti-anxiety effect of etifoxine thereby ruling out contribution of adrenal steroids. Thus, our results provide behavioral evidence for the role of neurosteroids like ALLO in the anti-anxiety effect of etifoxine.

[xptriado]

Ok this is thus far, next to ganaxolone, the most interesting thing IMO.

So, now my questions:

• Is it readily available on pharmacies?
• How can I get my doctor to prescribe it…

By the way, that GHB thing, how did you guys get your hands on it?

[braziliandude]

has anyone ever heard of this?

longecity.org/forum/topic/63 … periments/

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[dannyfc]

@xptriado

Ok this is thus far, next to ganaxolone, the most interesting thing IMO.

So, now my questions:

• Is it readily available on pharmacies?
• How can I get my doctor to prescribe it…

By the way, that GHB thing, how did you guys get your hands on it?

Yeah you can get it on online pharmacies. It’s popular in continental europe as an anti-anxiety treatment.

I’m not holding out too much hope but will be interesting to see if theres anything effect. I do think it targets the right mechanism, its funny how often finasteride is used in studies to counteract it’s effects. But I think the doses required for it to be effective are an issue, since it’s pretty heavy on the liver. Ganaxolone is probably the real lifeline. Unfortunately I imagine that won’t be on the market for another 2-3 years.

I wouldn’t bother with GHB if I’m honest. Feels more neurotoxic than beneficial.

[xptriado]

I’ve read that Sodium Oxybate, the GHB, is actually produced in our bodies. I’ve read it’s not neurotoxic at all but the problem is getting the dosages right because apparently it is not a linear or logarithmic progression in the effect aas you increase the dosage, but rather something exponential. Bear in mind this was what I read yesterday in a blog on how to make your own GHB so this is by no means something I read in a scientific study.

Ganaxolone seems to be the real deal…

I live in europe but for my insomnia/anxiety I only got prescribed these:

• anti depressives
• benzodiazepines
• buspirone
• valproic acid

i have only tried the AD’s and the benzos…they’re not as useful for me as I thought they would be.

I had epilepsy crisis too when i was 12, and medicated 2 years on phenobarbital (OUCH…), so I want to try an AED for my insomnia/sleep. I’m going to a neurologist specialized in epilepsy and sleep on the 18th of December. I wish he’d prescribe me Pregabalin. I’ll suggest that and let you know…

I’ve been trying this homeopathic product Gelsemium Sempervirens 5CH because I had read on a sci study on mouses that it increases Allopregnanolone biosynthesis…well…it’s hard to say if it’s doing something or not. …

[Mark2012]

@braziliandude

It seems you can buy it here phfsupplements.com/celtic-dreams-20-ml.html

Has anyone else here tried allopregnanolone ?

[nopecia]

@xptriado

Will someone try it out? I think I’ll order the homeopathic one plus glycine

Homeopathy is bullshit. Please stop wasting time and money on pseudo science.

[xptriado]

I also dont believe in it but i found SCIENTIFIC studies about this particular substance and it was 5 euros On the pharmacy that is 10 meters fromy office, so i bought it. I hope thats ok for you…

[nopecia]

There’s nothing scientific about the concept of homeopathy, regardless of what substance it is.

[xptriado]

Too bad then that this was a study published on pubmed where they measured allopregnanolone before and after administration of the compound, in mice…

[jamielondon]

DannyFc, did you ever try Etifoxine?

[gennaro]

Is there a natural way -other than alcohol- to raise allo? Or get it to be produced etc I don’t know the exact word for it. I’ve just started to get muscle twitches and it’s driving me nuts!

edit: Found this: 4abettermemory.com/memory/hormon … in-health/

“…Allopregnanolone is a metabolite of progesterone which is produced in the body. Progesterone comes the master hormone pregnenolone, and pregnenolone is available in this country as a health food supplement. If you’ve attended one of my classes you learned of the importance of pregnenolone as well as the hormone it produces – DHEA, estrogen and testosterone in promoting brain health, and how these are dramatically reduced by age, but can be boosted with this simple supplement which costs less than $25…”

Sounded like a scam to me but is there any credibility? I’ve searched over forum and read some conflicting ideas.

[Grey_baron]

Etifoxine did not help me or do anything at all, I bought it from awake brain, I also have emoxypine but haven’t tried it yet

[jamielondon]

Just ordered etifoxine- worth a shot.