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haidut

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The patents on most SSRI drugs have either expired or are close to expiration. Lately, there have also been a number of high profile cases obtaining favorable court outcomes by blaming SSRI drugs for a host of human criminal behaviors or adverse health events. As such, Big Pharma is desperate to find the "next big thing" in depression treatment, and preferably without the terrible side effects of SSRI drugs. Back in the 1960s it was discovered that GABA agonists had not only anti-anxiety but also rapid antidepressant effects. At the time, a number of GABA agonist steroids were in use as general anesthetics and it was discovered that these steroids also had antidepressant effects. Further research revealed that the progesterone (and 5a-DHP) metabolite allopregnanolone is one of the most potent endogenous antidepressant steroids. Since then, a number of companies have been quietly working on bringing synthetic versions of allopregnanolone to the market. It looks like one of them is now very close to being approved as a "novel", fast-acting antidepressant and Scientific American is running a story on that steroid. If Brexanolone gets approved, I would not be surprised if allopregnanolone, 5a-DHP, and even progesterone get pulled from the market as competing drugs that erode Brexanolone's profits. I guess the good news is that Big Pharma is finally going full-Peat in most of its drug development efforts:):

PTSD in women is associated with a block in conversion of progesterone to the GABAergic neurosteroids allopregnanolone and pregnanolone measured in... - PubMed - NCBI
An Entirely New Type of Antidepressant Targets Postpartum Depression
"...Based on Mody’s research, a company called Sage Therapeutics has developed a new drug to treat postpartum depression. Administered intravenously, the medication elevates allopregnanolone. It does not target the GABA receptors directly but has a similar effect: Higher levels of the steroid help activate the receptors, keeping GABA at a healthy level. Two phase II clinical trials led by Meltzer-Brody at U.N.C. tested the new drug in severely depressed postpartum women and had successful outcomes, resulting in a significant improvement in the self-reported mood of 70 percent of the new mothers. Most striking, the effect occurred immediately after the drug was administered, and the benefits persisted for 30 days. The first two trials included a total of only 25 women but Sage has since conducted two phase III trials with a combined 246 postpartum women, and preliminary reports are promising. The drug, called Brexanolone, is now under review by the U.S. Food and Drug Administration. If approved, it would be one of the first antidepressants with a new mechanism of action developed in recent years. Beyond postpartum depression, Mody hopes these drugs could treat other types of hormonal depression such as premenstrual dysphoric disorder—an extreme version of premenstrual syndrome (PMS)—and depression around the time of menopause. Mody is also looking into whether nonhormonal depression in women is influenced by this system. Women are twice as likely to suffer from generalized depression than men, so it is possible there is a hormonal component to their depression outside the established periods of extreme hormone fluctuation."
 
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Vinero

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Anything that raises GABA has very strong antidepressant effects. Alcohol, phenibut, benzos etc. are very powerful mood enhancers, and can immediately (but temporary) cure learned helplessness. This is why most hypothyroid or stressed people get addicted to them. It's crazy why serotonin is thought to have anti-depressant effects. I have taken tryptophan and 5-HTP as an experiment and just became nauseaous, restless and felt weird. Tryptophan is slightly more sedative and relaxing, probably because a part converts to niacin which is sedating. But 5-HTP is pure poison, I don't know how anyone can ingest that daily and have antidepressant effects.
 
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ddjd

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Anything that raises GABA has very strong antidepressant effects. Alcohol, phenibut, benzos etc. are very powerful mood enhancers, and can immediately (but temporary) cure learned helplessness. This is why most hypothyroid or stressed people get addicted to them. It's crazy why serotonin is thought to have anti-depressant effects. I have taken tryptophan and 5-HTP as an experiment and just became nauseaous, restless and felt weird. Tryptophan is slightly more sedative and relaxing, probably because a part converts to niacin which is sedating. But 5-HTP is pure poison, I don't know how anyone can ingest that daily and have antidepressant effects.
but long term dont they (phenibut, benzos, alcohol) all lower GABA activity...
 

Vinero

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but long term dont they (phenibut, benzos, alcohol) all lower GABA activity...
Ofcourse, if u abuse them. As long as you take it only sporadically, like once a week after a stressful day, you can enjoy the high-GABA state without any GABA receptor downregulation
 

PecosRiver

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When legal steroids (like 5a-dhp) are taken off the market, what is the usual process? Is it instantaneous, or do they make an announcement and vendors / customers have 30/60/?? days to settle up?

@haidut :I would appreciate a heads up warning as soon as you get wind of this happening. (I just ordered two 5a-dhp's just in case ...)
 

Aymen

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do you think the antidepressant effect we feel after ejaculation is a result of increased Allopregnanolone ?
 

haidut

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When legal steroids (like 5a-dhp) are taken off the market, what is the usual process? Is it instantaneous, or do they make an announcement and vendors / customers have 30/60/?? days to settle up?

@haidut :I would appreciate a heads up warning as soon as you get wind of this happening. (I just ordered two 5a-dhp's just in case ...)

It entirely depends on FDA's whim. They usually sends warning letters and allows existing supplies to be sold. But there have been cases when the letters just ordered immediate discontinuation as it happened with the pyridoxamine fiasco. On average they give about 30 days notice, so if we get any letters I will let people know ASAP via the forum and will also send an email to all people who have ordered 5a-DHP from us in the past.
 
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alywest

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Low doses of SSRI's are known to raise allopregnanolone levels, by inhibiting the enzymes that convert it back into 5a-dhp:

"Scientists from the University of Bristol, UCL and the University of Sao Paolo-Ribeirao Preto in Brazil have shown in rats that the anti-depressant (fluoxetine) can inhibit a specific enzyme in the brain and could be used to alleviate symptoms of progesterone withdrawal such as PMS and possibly also postnatal depression.
The new research shows that the antidepressants such as fluoxetine inhibit the enzyme, which deactivates allopregnanolone, therefore maintaining the chemical balance of this in-built tranquilizer in the brain.

...Short term treatment with a low dose of fluoxetine immediately prior to the rat's premenstrual period not only raised brain allopregnanolone and prevented the development of PMS-like symptoms but also blocked the increase in excitability of brain circuits involved in mediating the stress and fear responses that normally occur during this phase of the cycle.
Surprisingly, in the case of rats, the effective dose of fluoxetine was well below that needed to produce anti-depressant effects. The effects of the drug were seen within hours of administration, unlike the two to three weeks of treatment normally needed when fluoxetine used to treat depression."

They are basing these new drugs on the mechanisms of the SSRI's at extremely low doses.
 

haidut

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Low doses of SSRI's are known to raise allopregnanolone levels, by inhibiting the enzymes that convert it back into 5a-dhp:

"Scientists from the University of Bristol, UCL and the University of Sao Paolo-Ribeirao Preto in Brazil have shown in rats that the anti-depressant (fluoxetine) can inhibit a specific enzyme in the brain and could be used to alleviate symptoms of progesterone withdrawal such as PMS and possibly also postnatal depression.
The new research shows that the antidepressants such as fluoxetine inhibit the enzyme, which deactivates allopregnanolone, therefore maintaining the chemical balance of this in-built tranquilizer in the brain.

...Short term treatment with a low dose of fluoxetine immediately prior to the rat's premenstrual period not only raised brain allopregnanolone and prevented the development of PMS-like symptoms but also blocked the increase in excitability of brain circuits involved in mediating the stress and fear responses that normally occur during this phase of the cycle.
Surprisingly, in the case of rats, the effective dose of fluoxetine was well below that needed to produce anti-depressant effects. The effects of the drug were seen within hours of administration, unlike the two to three weeks of treatment normally needed when fluoxetine used to treat depression."

They are basing these new drugs on the mechanisms of the SSRI's at extremely low doses.

True, and this effects on 3a-HSD combined with 5-HT2C antagonism that many SSRI drugs have is probably the main reason for their anti-depressant effects. But the Brexanolone is actually a synthetic version of allopregnanolone, so it does not work like fluoxetine on 3a-HSD even though the end effect is the same.
 

Jackrabbit

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True, and this effects on 3a-HSD combined with 5-HT2C antagonism that many SSRI drugs have is probably the main reason for their anti-depressant effects. But the Brexanolone is actually a synthetic version of allopregnanolone, so it does not work like fluoxetine on 3a-HSD even though the end effect is the same.
Do you think it will comparable to progestins in that the synthetic version will be toxic and basically worse for people than not taking it at all?
 

aguilaroja

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...Further research revealed that the progesterone (and 5a-DHP) metabolite allopregnanolone is one of the most potent endogenous antidepressant steroids. Since then, a number of companies have been quietly working on bringing synthetic versions of allopregnanolone to the market. It looks like one of them is now very close to being approved as a "novel", fast-acting antidepressant and Scientific American is running a story on that steroid. If Brexanolone gets approved, I would not be surprised if allopregnanolone, 5a-DHP, and even progesterone get pulled from the market as competing drugs that erode Brexanolone's profits. I guess the good news is that Big Pharma is finally going full-Peat in most of its drug development efforts:):

An Entirely New Type of Antidepressant Targets Postpartum Depression
"...Beyond postpartum depression, Mody hopes these drugs could treat other types of hormonal depression such as premenstrual dysphoric disorder...and depression around the time of menopause. Mody is also looking into whether nonhormonal depression in women is influenced by this system."

This finding was reported a few months ago:

PTSD in women is associated with a block in conversion of progesterone to the GABAergic neurosteroids allopregnanolone and pregnanolone measured in... - PubMed - NCBI
“Allopregnanolone and its stereoisomer pregnanolone (together termed ALLO) are metabolites of progesterone that positively and allosterically modulate GABA effects at GABAA receptors, thereby reducing anxiety and depression. Previous research revealed that women with PTSD had low cerebrospinal fluid (CSF) ALLO levels and a low ratio of ALLO to the allopregnanolone precursor 5α-DHP, consistent with deficient activity of the ALLO synthetic enzyme 3α-hydroxysteroid dehydrogenase (3α-HSD).”

“Results indicate that the ALLO to 5α-DHP ratio in plasma increases between the eFP and mLP. In addition, women with PTSD have a lower ratio of ALLO to 5α-DHP than trauma-exposed healthy women, as well as blunted increases in this ratio in response to a moderately stressful laboratory procedure, i.e., differential fear conditioning, across the menstrual cycle.”
 

haidut

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This finding was reported a few months ago:

PTSD in women is associated with a block in conversion of progesterone to the GABAergic neurosteroids allopregnanolone and pregnanolone measured in... - PubMed - NCBI
“Allopregnanolone and its stereoisomer pregnanolone (together termed ALLO) are metabolites of progesterone that positively and allosterically modulate GABA effects at GABAA receptors, thereby reducing anxiety and depression. Previous research revealed that women with PTSD had low cerebrospinal fluid (CSF) ALLO levels and a low ratio of ALLO to the allopregnanolone precursor 5α-DHP, consistent with deficient activity of the ALLO synthetic enzyme 3α-hydroxysteroid dehydrogenase (3α-HSD).”

“Results indicate that the ALLO to 5α-DHP ratio in plasma increases between the eFP and mLP. In addition, women with PTSD have a lower ratio of ALLO to 5α-DHP than trauma-exposed healthy women, as well as blunted increases in this ratio in response to a moderately stressful laboratory procedure, i.e., differential fear conditioning, across the menstrual cycle.”

Thanks, I could not find the actual study. I will put it in the OP.
 

haidut

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Do you think it will comparable to progestins in that the synthetic version will be toxic and basically worse for people than not taking it at all?

Brexanolone is actually one of the names of allopregnanolone but it is also used to refer to its 3b-methyl ester. If it is the latter (which is synthetic and thus patentable) then its toxicity will depend on how well the liver handles 3b-methylated steroids and whether it would affect the synthesis of endogenous steroids like pregnenolone, progesteron and DHEA. None of these studies have been done yet (to my knowledge) so it is too early to say.
 

alywest

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True, and this effects on 3a-HSD combined with 5-HT2C antagonism that many SSRI drugs have is probably the main reason for their anti-depressant effects. But the Brexanolone is actually a synthetic version of allopregnanolone, so it does not work like fluoxetine on 3a-HSD even though the end effect is the same.
Thanks for clarifying that, Haidut!
 
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lollipop

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@haidut do you really think they could take progesterone like Progest-e, creams etc. off the market? Wouldn’t there be such a HUGE backlash?
 

haidut

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@haidut do you really think they could take progesterone like Progest-e, creams etc. off the market? Wouldn’t there be such a HUGE backlash?

Banning progesterone altogether will probably be more difficult but it is not out of the question. Human studies showed reliable allopregnanolone elevations following repeated low-dose progesterone administration (50mg x 2-3 times daily). So, it all depends on how much profit the pharma company determines is being lost due to people flocking to progesterone. As far as 5a-DHP and and allopregnanolone, I have no doubt they will be pulled if Brexanolone gets approved. They are more obscure than progesterone and not many people (even doctors) know about them. Remember that FDA banned pyridoxamine quite easily. If it can ban a naturally occurring B6 isomer, nothing is out of reach for the corrupt government arm of pharma companies.
 
L

lollipop

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Banning progesterone altogether will probably be more difficult but it is not out of the question. Human studies showed reliable allopregnanolone elevations following repeated low-dose progesterone administration (50mg x 2-3 times daily). So, it all depends on how much profit the pharma company determines is being lost due to people flocking to progesterone. As far as 5a-DHP and and allopregnanolone, I have no doubt they will be pulled if Brexanolone gets approved. They are more obscure than progesterone and not many people (even doctors) know about them. Remember that FDA banned pyridoxamine quite easily. If it can ban a naturally occurring B6 isomer, nothing is out of reach for the corrupt government arm of pharma companies.
Urrrgh :-/ fingers crossed
 

haidut

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Is Allopregnanolone available to buy as a stand-alone supplement anywhere?

Major chemical vendors like Sigma Aldrich sell it, but it is very expensive and even then the amounts sold usually do not exceed 50mg. Most animal studies used the equivalent of 5mg-20mg daily, so it becomes prohibitively expensive. That one of the reasons I did not release ALLO as a product but its direct precursors 5a-DHP, which is (a bit) more affordable.
 
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