Androsterone - Anxiolytic, Sedative, And Anti-Convulsant Neurosteroid

haidut

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I just posted a thread about androsterone and its potent anti-depressant effects:
Androsterone - An Andidepressant Neurosteroid

Just like allopregannolone (ALLO), androsterone is 5-AR derived neurosteroid, and just like allopreganolone androsterone is a very potent GABA agonist (even more potent than progesterone). Allopregnanolone has been in human clinical trials for everything from anxiety, to depression, to seizures, to schizophrenia, to autism, etc. The medical industry is so in love with allopregnanolone that it came up with a synthetic version (ganaxolone) and patented it with the excuse that allopregnanolone has a very short half life and quickly disappears from bloodstream. Yes, that is true, and it is an indication of how much the tissues want to accumulate ALLO.
Ganaxolone - Wikipedia, the free encyclopedia

Anyways, the neurosteroid androsterone, which is a metabolite of DHT, has virtually the same benefits profile as ALLO and at least for now it is not in danger of being patented. The studies below show its effects as a GABA agonist and in treatment of anxiety, seizures, and mental hyperactivity (sedating effect).

The effect of age on the discriminative stimulus effects of ethanol and its GABA(A) receptor mediation in cynomolgus monkeys. - PubMed - NCBI
"...RESULTS: Two of the naïve middle-aged monkeys attained criterion performance, with weak stimulus control and few discrimination tests, despite greater blood-ethanol concentration 60 min after 1.0 g/kg ethanol in middle-aged compared to young adult female monkeys (Green et al. in Alcohol Clin Exp Res 23:611-616, 1999). The efficacy of the GABA(A) receptor positive modulators pentobarbital, midazolam, allopregnanolone, pregnanolone, and androsterone to substitute for the discriminative stimulus effects of 1.0 g/kg ethanol was maintained from young adulthood to middle age."

Interaction of androsterone and progesterone with inhibitory ligand-gated ion channels: a patch clamp study. - PubMed - NCBI
"...A direct activation of inhibitory ionotropic receptors was observed for androsterone at GABA(A) receptor channels. A coactivation of currents elicited by nonsaturating agonist concentrations was observed with androsterone and progesterone at glycine andGABA(A) receptor channels. We could show that association of beta subunits with alpha subunits affects the sensitivity of glycine receptors toandrosterone."

The neurosteroid dehydroepiandrosterone (DHEA) and its metabolites alter 5-HT neuronal activity via modulation of GABAA receptors. - PubMed - NCBI
"...DHEA (100 μM) and DHEA-S (100 μM) also attenuated the effect of GABA. Androsterone (10 and 30 μM) markedly enhanced the inhibitory response to THIP (25 μM). The effect was apparent during androsterone administration but persisted and even increased in magnitude after drug wash-out. The data indicate that GABA(A) receptor-mediated regulation of 5-HT neuronal firing is sensitive to negative modulation by DHEA and its metabolite DHEA-S is sensitive to positive modulation by the metabolite androsterone. The effects of these neurosteroids on GABA(A) receptor-mediated regulation of 5-HT firing may underlie some of the reported behavioural and psychological effects of endogenous and exogenous DHEA."

Androgens with activity at estrogen receptor beta have anxiolytic and cognitive-enhancing effects in male rats and mice. - PubMed - NCBI
"...Both rats and wildtype mice, but not betaERKO mice, consistently had reduced anxiety and improved performance in the object recognition task. Androsterone was only effective at reducing anxiety-like behavior in the elevated plus maze and this effect was modestly reduced by flumazenil administration. Thus, actions at ERbeta may be required for T's anxiety-reducing and cognitive-enhancing effects."

Testosterone rapidly reduces anxiety in male house mice (Mus musculus). - PubMed - NCBI
"...In Experiments 5 and 6, 3alpha,5alpha-reduced neurosteroid metabolites of testosterone (androsterone and 3alpha-androstandione) were both anxiolytic at a lower dosage (100 microg/sc injection) than testosterone, supporting the notion that testosterone is converted into neurosteroid metabolites for anxiolytic activity. Experiments 7 and 8 found that either picrotoxin or bicucculine, noncompetitive and competitive antagonists of the GABA(A) receptor, respectively, blocked the anxiolytic effects of testosterone. However, conclusions from these 2 experiments must be tempered by the reduction in locomotor activity that was also seen. The possible brain locations of testosterone action as well as the possible adaptive significance of this anxiolytic response are discussed."

Diurnal variation in the proconvulsant effect of 3-mercaptopropionic acid and the anticonvulsant effect of androsterone in the Syrian hamster. - PubMed - NCBI
"...In this study we have examined rhythms in the proconvulsant effect of inhibition of glutamate decarboxylase (GAD) in hamsters (Mesocricetus auratus) as well as the anticonvulsant effect of androsterone, a neurosteroid that positively modulates the GABA(A) receptor. Administration of 10-60 mg/Kg of 3-mercaptopropionic acid (3-MPA, a GAD inhibitor) induced convulsions that were analyzed by an ad-hoc severity scale, with a lower sensitivity threshold at 24:00 h. Moreover, the latency for first and maximal convulsive response times was significantly lower at night. A similar temporal profile (maximal effect at midnight) was found for picrotoxin-induced seizures. Androsterone (40 mg/Kg) completely inhibited 3-MPA-induced tonic/clonic seizures at 12:00 h, while it had a partial inhibitory effect at 24:00 h. These results support the importance of temporal regulation of GABAergic modulation in the central nervous system."

[Steroid modulation of GABA(A) receptors]. - PubMed - NCBI
"...It has been known for many years that steroids influence many processes by genome activation. In 40-th the fast (anesthetic)-effect of steroids on neuronal activity was discovered, and later the molecular mechanism of steroid action as modulators of GABA(A) receptors was documented. Such kind of influence of neuronal activity is characteristic for some glucocorticosteroids and some derivatives of androsterone and progesterone (for instance: THDOC, THP). The endogenous production of several steroids in the brain was proved. Recently modulatory effect (anti-anesthetic properties) of sulphate esters of pregnenolone (P) and dehydroepiandrosterone (DHEA) on GABAA receptors was discovered. The steroid influence on the neuronal activity is still poorly documented and requires further investigations."

Modulation of the GABAA receptor by depressant barbiturates and pregnane steroids. - PubMed - NCBI
"...The modulation of the gamma-aminobutyric acidA (GABAA) receptor by reduced metabolites of progesterone and deoxycorticosterone has been compared with that produced by depressant barbiturates in: (a) voltage-clamp recordings from bovine enzymatically isolated chromaffin cells in cell culture, and (b) an assay of the specific binding of [3H]-muscimol to a preparation of porcine brain membranes. 2. The progesterone metabolites 5 alpha- and 5 beta-pregnan-3 alpha-ol-20-one (greater than or equal to 30 nM) reversibly and dose-dependently enhanced the amplitude of membrane currents elicited by locally applied GABA (100 microM), and over the concentration range 30 nM-100 microM stimulated the binding of [3H]-muscimol. In contrast, 5 alpha- and 5 beta-pregnan-3 beta-ol-20-one (30 nM-100 microM) had little effect in either assay, indicating a marked stereoselectivity of steroid action. 3. Scatchard analysis of the ligand binding data suggested an apparent increase in the number, rather than the affinity, of detectable [3H]-muscimol binding sites as the principle action of the active steroid isomers. 4. GABA-evoked currents were also potentiated by androsterone (1 microM) and the deoxycorticosterone metabolite 5 alpha-pregnane-3 alpha,21-diol-20-one (100 nM)."

Finally, it seems that in men androsterone is the MAIN neurosteroid with GABA agonist activity and lower levels are found in many males with schizophrenia. Effective anti-psychotic drugs often restore levels of androsterone to normal.

Altered levels of circulating GABAergic 5α/β-reduced pregnane and androstane steroids in schizophrenic men. - PubMed - NCBI
"...The role of GABAergic pathways in the pathophysiology of schizophrenia is generally accepted. Therefore, the information concerning alterations of the steroid metabolome associated with the disease and/or its treatment is of interest with regard to the pathophysiology of the disease. Hence, we assessed 18 serum steroids and steroid polar conjugates in a group of drug-naive patients (13 adult men) and after 6-months therapy by atypical antipsychotics and age-matched controls (19 men) using gas chromatography-mass spectrometry analysis. This study, for the first time, demonstrates the altered circulating GABAergic steroids in schizophrenic men as well as the effect of the therapy with two types of atypical antipsychotics. The GABAergic androsterone (3α5α) and etiocholanolone (3α5β) are reduced in schizophrenic men but the therapy with atypical antipsychotics reinstates their levels. This reinstatement could be of importance when considering that the GABAergic substances generally improve the well-being of patients. In addition to the unconjugated androsterone, being the most abundant GABAergic steroid in men, most of the other GABAergic steroids also tended to decrease in the patients. By contrast, the conjugated 5β-pregnanolone isomers were elevated in the patients. In conclusion, although schizophrenia status in adult men is associated with unfavorable alterations in neuroactive steroids, the treatment with antipsychotics could at least partly reinstate their circulating levels. "
 
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allblues

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Oh, and have you seen any info on if/how Androsterone affects the HPTA axis?
 

DaveFoster

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But wait, testosterone causes anger don't you know? Don't you know men are supposed to be angry?
 

Tarmander

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Pretty interesting. I found this on wiki:

"Specific substrates include testosterone, progesterone, androstenedione, epi-testosterone, cortisol, aldosterone, and deoxycorticosterone. Outside of dihydrotestosterone, much of the physiological role of 5α-reduced steroids is unknown."

Is there a pretty reliable list of all the hormones that 5-AR interacts with? Testosterone seems to be the main one, as well as allopreg and androsterone.
 

haidut

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haidut

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haidut

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Oh, and have you seen any info on if/how Androsterone affects the HPTA axis?

Well, it lowers adrenaline release.
Androsterone Inhibits Catecholamine Release

It is also a GABA agonist and GABA agonists are used clinically for managing Cushing syndrome since they reduce cortisol. So, given that it is sedative and anti-depressant (i.e. cortisol causes depression) I suspect it inhibits excessive HPTA activity.
 

haidut

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Pretty interesting. I found this on wiki:

"Specific substrates include testosterone, progesterone, androstenedione, epi-testosterone, cortisol, aldosterone, and deoxycorticosterone. Outside of dihydrotestosterone, much of the physiological role of 5α-reduced steroids is unknown."

Is there a pretty reliable list of all the hormones that 5-AR interacts with? Testosterone seems to be the main one, as well as allopreg and androsterone.

This is a very good question. And the answer is nobody knows the full list of hormones 5-AR interacts with. If you look at this thread, I uploaded two images showing the newly discovered "backdoor" and "alternative" pathways for synthesizing androgens.
Androsterone - Androgenic, Anti-estrogenic, Thyromimetic Neurosteroid
The shocking news to me is that the steroid allopregnanolone, which was considered a terminal metabolite of progesterone is also a pro-hormone to DHT! It makes good sense for it to be as it is also a 5-AR derived steroids and they all seem to interconvert into each other. It suggests that allopregnanolone may also be androgenic, anti-estrogenic, and even anabolic like some of the 5-AR derived androgens. Very exciting and this is just beginning to be unraveled.
 

allblues

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I'm sorry, i probably got the acronym wrong. What i meant to ask was - will androsterone "shut you down", as a guy, ie shut down
endogenous testosterone/androgen production, at all?

Edit; I see now you've adressed this in the product thread.
 
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Pointless

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This sounds like it might produce a dependency. Can it be addictive like phenibut?
 

haidut

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This sounds like it might produce a dependency. Can it be addictive like phenibut?

Why would it produce a dependency? Via what mechanism or effect?
 

Pointless

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Why would it produce a dependency? Via what mechanism or effect?

Good question. Now I have to find a reference. Here's one:

Use-dependent regulation of GABAA receptors. - PubMed - NCBI

"Components of the GABAA receptor downregulation pathway are also evoked by chronic administration of GABAmimetics, benzodiazepines, barbiturates, and neurosteroids in animals. This downregulation correlates with the establishment of tolerance to and physical dependence on the pharmacological effects of these drugs"

That FXR agonism you posted about is tempting, though. It seems to fit very closely with my situation. The study specifically names neurosteroids. Any tips on avoiding this possibility or what to do if GABA becomes downregulated?
 

haidut

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Good question. Now I have to find a reference. Here's one:

Use-dependent regulation of GABAA receptors. - PubMed - NCBI

"Components of the GABAA receptor downregulation pathway are also evoked by chronic administration of GABAmimetics, benzodiazepines, barbiturates, and neurosteroids in animals. This downregulation correlates with the establishment of tolerance to and physical dependence on the pharmacological effects of these drugs"

That FXR agonism you posted about is tempting, though. It seems to fit very closely with my situation. The study specifically names neurosteroids. Any tips on avoiding this possibility or what to do if GABA becomes downregulated?

I think the dependence is mostly related to synthetic drugs like the benzodiazepines. I have not heard of anyone get dependence from say allopregnanolone, progesterone or even Ganaxolone (the patented synthetic allopregnanolone). These are the most potent GABA agonists in existence and none of them is known to produce dependence. I thin the issue is with specificity. Drugs that only act like GABA agonists have withdrawal effects through downregulation. The neurosteroids have mechanisms to balance this downregulation like simultaneous downregulation of glutamate synthesis so even if you stop taking them your glutamate levels will also be low and you won't experience a relative GABA deficiency. Then everything recovers together nicely. The synthetic GABA agonists rarely have such systemic balancing/protective effects.
 
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DaveFoster

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@allblues

Have you tried androsterone yet, and have you experienced any shutdown?
 

allblues

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I did use it on and off for about 3 weeks after coming off the DHT and while still dealing with some suppression.
It wouldn't say it made it worse but i didn't see enough progress with the suppresion to dare take anymore non-basic steroids,
so i quit using it and haven't since.

I did like it though. Still trying to figure out my steroid- and general health situation so i'm sticking to the basics for now.
 

SonOfEurope

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The masculine and confident relaxation, the clear-as-water mind and organized thought pattern I get (and assume most men get) from as little as 2mg Androsterone is blatantly obvious, it is the exact opposite of the mentally hyper excited and "dementia-like" excitation you would get from elevated E2.

In that sense it even beats progesterone in a short burst so much it's amazing, especially combined with caffeine and thyroid.

With that said I'll just leave my last advice which is to keep it below 6mg/day. I received my bottle yesterday along with my cortinon (8:1) my Daily Dose is 16mg P4, 2mg DHEA and 3mg Andro though not everyday, I'm cutting very well by watching macros and calories as adviced by @Hans and should be at 10% by July. Thank you for the excellent quality of your products, Haidut.!

Let's only hope the tyrant Big Pharma doesn't "patent" (hijack) them any time soon...
 
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