FDA Approves Allopregnanolone As A Fast-acting, Long-lasting Antidepressant

['peataphysique]

lol, i guess either exploit the ''system" as it presents itself, or indulge the theme of disempowered victim...BUT anyway, from an empowered perspective, agmatine is just the decarboxylates form of common OTC amino acid Arginine. PEA is OTC available world-wide. There's countless other PPAR-alpha activators, ofc.

Easy OTC ways for increasing natural production of Allopregnanolone: Agmatine & Palmitoylethanolamide
(They have countless other biological properties, which are complementary to longevity an quality of life etc)

Palmitoylethanolamide is also a potent PPAR-α activator.
Palmitoylethanolamide (PEA) is synthesized from the same class of membrane phospholipids, the N-acylphosphatidylethanolamines, that are precursors for Anandamide. PEA is primarily catabolized by NAAA enzyme but is also a substrate for FAAH. PEA is an agonist at the peroxisome proliferator-activated receptor α (PPARα) but has no activity at the CB1R.

Palmitoylethanolamide is actually (normally) co-released alongside other endogenous cannabinoids, but sometimes this can malfunction. Palmitoylethanolamide is potent at reducing mast cell/histamine & general allergy related dynamics:

Will check this out.

 

[Sativa]

That is contingent on your values. If one values the truth then one can certainly reflect on the quality of that truth IE empowering or disempowering, but ultimately go on to excavate this truth and find Solutions to better one's life. I think often people mistake beneficial or empowering for "truth."

Perhaps it's more comfortable (& familiar?) to stay torn!

 

[jb116]

Perhaps it's more comfortable (& familiar?) to stay torn!

I think you misunderstand. It's not about a general victim mentality but an awareness. Think, act, perceive would have no meaning otherwise. You can reduce it psychologically if you want to but it's a waste of time and serves no real purpose. One can easily turn around and say it's comfortable and familiar to be delusional or intentionally blind to adversity.

It's about understanding the reality of a situation and thinking of solutions. That's mindfulness. To be torn over a situation where options can be taken away is simply being mindful of nefarious things around us. That's why we're here in this forum.

 

[Sativa]

Agmatine increases cAMP levels, which activates PPAR-alpha & PGC1-alpha, thus directly stimulating Allopregnanolone.
PDE4 inhibitor's raise cAMP levels, and would also stimulate Allopregnanolone production.
(forskolin, luteolin, artichoke extract & caffeine all raise cAMP levels - forskolin directly, the rest are PDE4i's)

re Agmatine:
Our previous investigation indicates that Agmatine increases cellular [cAMP] (3, 6).
This finding led to the hypothesis that Agmatine may have a widespread influence on whole body metabolic profiling by elevating the intracellular cAMP level.
One of the many metabolic functions known to be impacted by cAMP signaling is the activation of gene expression and its action on both the peroxisomal proliferator-activated receptor-α (PPARα) and its coactivator, PGC1α.

Another way to raise cAMP levels is using a PDE4 inhibitor.

PDE4 hydrolyzes cyclic adenosine monophosphate (cAMP) to inactive adenosine monophosphate (AMP). Inhibition of PDE4 blocks hydrolysis of cAMP, thereby increasing levels of cAMP within cells.

Coleus Forskohlii activates the enzyme adenylyl cyclase which then increases intracellular levels of cAMP.

More insight on Agmatine (from my main thread on it)

Agmatine stimulates the endogenous synthesis of allopregnanolone via activation of the PPAR-α receptor & PGC1α! (paper attached)

- The molecular and metabolic influence of long-term Agmatine consumption -
Subsequently, Agmatine induced a widespread impact on gene expression and metabolic profiling, including: (a) activation of PPARα, and its coactivator PGC1α; (b) increased expression of PPARγ and genes regulating thermogenesis, gluconeogenesis, and carnitine (Car) biosynthesis and transport.
________________________
Paper PDE4 enzyme & role
PDE4 as a target for cognition enhancement

Incidentally, increasing cAMP levels, and reducing PDE4 will [temporarily] counter-act sleep-deprivation symptoms:

The study showed that mice deprived of sleep had increased levels of the enzyme PDE4 and reduced levels of the molecule cAMP, the latter of which is crucial in forming new synaptic connections in the hippocampus, a physiological hallmark of learning.

 

[LeeLemonoil]

Dont know if higher cAMP really necessarily means higher Allo synthesis. It is a necessary mechanism but not a sufficient one.
In and case an interesting substance, agmatine. Sounds like it would also increase mitogenesis via ppra and pcg.

 

[Sativa]

Agmatine stimulates the endogenous synthesis of allopregnanolone via activation of the PPAR-α receptor & PGC1α

Agmatine increases cellular [cAMP] (3, 6)
...One of the many metabolic functions known to be impacted by cAMP signaling is the activation of gene expression and its action on both the peroxisomal proliferator-activated receptor-α (PPARα) and its coactivator, PGC1α.

The endocannabinoid/fatty acid amide 'palmitoylethanolamide' also stimulates endogenous synthesis of allopregnanolone, via the same mechanisms (PPARa & PGC1a). PEAmide is pretty neat itself. It's an endogenous inhibitor of mast cell degranulation (iirc), implying vastly reduced histamine. Naturally it's a potent anti-inflammatory.

 

[sladerunner69]

There was a similar thread from 2018 with some good discussion. I bought PEA at that time because my mom was ill on hospice and I was experiencing some issues related to the stress of that experience. I tried it again today thanks to your post serving as a reminder! It helped me finally get some nice restorative sleep that had been alluding me since going back to night shift work.
Allopregnanolone May Soon Be Approved As A Fast-acting Antidepressant

I'm sorry but I am having trouble understanding that quote. (I have a bad headache, which is unfortunately quite common for me)

So PEA is a reliable way to increase allpregnenalone? Or to activate the same neurological pathways?

I ahve post finasteride syndrome and would definitely like to try some allopregnanolone because pregnanolone and 5adhp have helped me in the past. Anything that increases GABA is helpful, it seems. Too much can cause a headache, though.

 

[Blossom]

I'm sorry but I am having trouble understanding that quote. (I have a bad headache, which is unfortunately quite common for me)

So PEA is a reliable way to increase allpregnenalone? Or to activate the same neurological pathways?

I ahve post finasteride syndrome and would definitely like to try some allopregnanolone because pregnanolone and 5adhp have helped me in the past. Anything that increases GABA is helpful, it seems. Too much can cause a headache, though.

I’ll try to explain it the best I can- palmitoylethanolamine is supposed to boost allopregnanolone via ppar-alpha.

@alywest presented some studies in the link above. I’ve also tried agmatine and it seems helpful as well. @Sativa has been discussing this recently as another way of boosting production of allopregnanolone. I used the palmitoylethanolamine that I had left and feel like it helped with the depression like symptoms I was having from starting back on night shift (which all seemed stress related). I’ve not reordered palmitoylethanolamine yet and have just been using agmatine. I don’t always remember to take it so hopefully I just needed it short term to get me over the hump so to speak.

 

[rob]

@Sativa Many thanks for the info on PEA and agmatine, both had completely passed me by.

My Crohn's is in remission but cognitive and nervous system issues are still a work in progress (go from mentally bored and symptoms of fatigue – to the point where my legs will physically begin to hurt if standing still – to mental overexcitability, tension and surges in adrenaline). With its supposedly improved bioavailability, it will be interesting to see if the Levagen PEA I just ordered helps at all. On the face of it, the FAAH and NAAA antagonism/endocannabinoid system-mediated anti-inflammatory benefits plus allopregnanolone upregulation looks like a great combo – I noted some promising studies regarding intestinal health.

Look forward to researching these compounds more.

N.B. Upon further reading, interesting to see PEA's potent inhibition of mast cells given that CRH release, which alloprognenolone antagonises, mediates its peripheral pro-inflammatory effects via mast cell activation.

 

[Sativa]

PEA's potent inhibition of mast cells given that CRH release, which alloprognenolone antagonises, mediates its peripheral pro-inflammatory effects via mast cell activation.

Thanks for that insight showing CRH activates mast cells.

CRH is the final common element that directs the body’s response to many forms of stress, including physical/emotional stresses & external/internal stresses.

I think this automatically promotes PEAmide (and likely Agmatine), alongside Salicylic acid, caffeine, progesterone, gelatin, succinic acid, methylene blue, pyroglutamic acid, magnesium, calcium, CoQ10, vitamin E, D, B3, B1 as top strategic ways to balance dysfunctional metabolism by counteracting estrogen overstimulation & overactive cortisol stress systems (in part by mitigating the excitatory toxic effects of adrenaline by by hyper-stimulating glutamate cells, via direct glutamate inhibition, but also promoting GABA function which has an overall inhibitory role).

By the way, there's no need to pay extra for expensive 'ultra-micronsed' palmitoylethanolamine, regular pea works perfectly well.

 

[TheBeard]

As many of forum users know, one of the real mechanisms of action of the SSRI drugs is not the increased serotonin but the increase in brain allopregnanolone these drugs cause. As such, there has been (secret) interest from Big Pharma for years in both allpregnanolone and its synthetic derivatives as antidepressant drugs. I posted not long ago on the fact that FDA was looking at approving allopregnanolone as antidepressant.
Allopregnanolone May Soon Be Approved As A Fast-acting Antidepressant

Well, now it appears that FDA has made up its mind and has approved allopregnanolone (Brexanolone) as a fast-acting antidepressant for post-partum depression. The fact that works so rapidly (within 24 hours) makes it that much more attractive as depression treatment, especially in suicidal cases. Even more stunningly, the relief from depression lasted at least 30 days after the single infusion of the steroid. This synthetic steroid now has the potential to dwarf the sales of SSRI drugs that are falling (slowly) our of favor, take up to 4 weeks to produce effects, actually increase risk of suicide, and do not work on 40%-60% of the patients taking them.
While the approval is specifically for post-partum depression, this allows any doctor to prescribe it semi-off-label for depression due to any cause. This is both good and bad news. The good news is that pharma companies and FDA are finally starting to change science in a positive direction. The bad news is that now allopregnanolone is a prescription drug and its precursors like 5a-DHP, progesterone and even pregnenolone may become target for FDA to withdraw from market as effective precursors to the now-prescription drug allopregnanolone. All 3 have been shown to reliably increase allopregnanolone levels in the brain and the last two have decent evidence from human studies too.

‘Transformative’: FDA approves first drug for postpartum depression
"...But on Tuesday, the Food and Drug Administration approved the first drug specifically developed for postpartum depression, called brexanolone, or Zulresso. Brexanolone is novel because it has a synthetic form of the hormone allopregnanolone, a progesterone derivative, in it. The hormone increases throughout a woman’s pregnancy and then plummets after she gives birth, a possible contributor to postpartum depression."

"...In double-blind, placebo-controlled trials, many women with moderate to severe postpartum depression saw a marked improvement of their symptoms within just 24 hours of receiving the drug. That improvement was still present 30 days after the infusion, the length of the trial. “This is for postpartum depression, but it is a step in understanding how we treat depression more broadly,” said Dr. Samantha Meltzer-Brody, director of the perinatal psychiatry program at the University of North Carolina at Chapel Hill and the academic principal investigator in the brexanolone trials. “We have had the same treatments for depression for 30 years. There’s an enormous need for new, novel ways to treat depression, and to treat it quickly.”

Does exogenous testosterone upregulate allopregnanolone?

 

[rob]

Thanks for that insight showing CRH activates mast cells.

Yeah, spent a while last year connecting dots on how neurogenic factors influenced bioenergetics and vice versa with my Crohn’s. On reflection, could have saved myself a lot of time if I’d found Ray’s works and these forums first :)

It’s interesting to note that many ‘autoimmune’ diseases have a high number of mast cells in the inflamed tissue. Moreover, studies have now shown that CRH potently reduces intestinal integrity, which naturally allows for luminal bacteria and food antigens to translocate and provoke an immune response deleterious to healthy tissue. Honestly, wouldn’t be surprised if MC degranulation played a part in the adverse microbiome shifts you see in stressed subjects.

Mast cell stabilisers definitely look like another option alongside GABA agonists/CRH antagonists.

I think this automatically promotes PEAmide (and likely Agmatine), alongside Salicylic acid, caffeine, progesterone, gelatin, succinic acid, methylene blue, pyroglutamic acid, magnesium, calcium, CoQ10, vitamin E, D, B3, B1 as top strategic ways to balance dysfunctional metabolism by counteracting estrogen overstimulation & overactive cortisol stress systems (in part by mitigating the excitatory toxic effects of adrenaline by by hyper-stimulating glutamate cells, via direct glutamate inhibition, but also promoting GABA function which has an overall inhibitory role).

By the way, there's no need to pay extra for expensive 'ultra-micronsed' palmitoylethanolamine, regular pea works perfectly well.

Yep, supporting energy metabolism/mitochondria is critical - this is how I got into remission at the end of 2018 with, in particular, nicotinamide riboside to help better meet the demands of stressors.

Of course, the mitochondria are also where cholesterol kicks off for the neurosteroids so it’s win-win. Wouldn’t be surprised if some of the benefits people are experiencing with B1 (esp. the likes of allithiamine) is from supporting the pentose phosphate pathway/ NADPH production as a lot of the steps in steroid synthesis require NADPH.

Also on the coq10 you listed, the promising results of mitochondrial-targeted antioxidants, such as SkQ, in models of chronic inflammatory disease are another good indicator of the role bioenergetics/mitochondrial dysfunction plays.

 

[Sativa]

Mast cell stabilisers definitely look like another option alongside GABA agonists

Aside: I wouldn't recommend the [long-term] use of synthetic direct GABA agonists , since these are prone to resulting in a natural response of the body reducing the amount of targeted GABA receptors (via a process called down-regulation); the result would include withdrawal.
A more strategic & sustainable approach would be to use substances which act in a more sustainable way, such as Positive Allosteric Modulator's (PAM) or perhaps a GABA transaminase inhibitor. (Inhibiting the GABA transaminase enzymes reduces the degradation of GABA, leading to increased GABA concentrations). Maybe constant use of this type of inhibitor might also cause similar withdrawal issues in the long-term...

Other options include Kava, an enjoyable & unique botanical which upregulates GABA, and Magnolia Bark, which potentiates GABA & has therapeutic cannabinoid properties.

Progesterone, niacinamide, taurine, SFA, aspirin, thyroid, etc all have a direct role in increasing pro-GABA tone and opposing excessive excitation.

Wouldn’t be surprised if some of the benefits people are experiencing with B1 is from supporting the pentose phosphate pathway/ NADPH production as a lot of the steps in steroid synthesis require NADPH.

Yes, NADH/NADPH is a prime are of focus & enhancement of various recommended therapeutic substances on these forums.
The user Haidut has created countless informative threads on this entire area; they pretty much include everything you need to know, or what areas to further explore to get the answers you're looking for.

Of course, the mitochondria are also where cholesterol kicks off for the neurosteroids so it’s win-win.

btw, a precursor to cholesterol is 'Squalane', found in olive oil. Fairly inexpensive.
It's probably useful for people who want to enhance the cholesterol & neurosteroids production. For the vegan's out there, who restrict themselves from dietary animal cholesterol, Squalane is a perfect solution.

 

[Inaut]

A little off topic but related to squalane..... @Sativa do you think it is an ideal carrier oil? For essential oils and other compounds? Moreso then olive oil?

 

[rob]

Aside: I wouldn't recommend the [long-term] use of synthetic direct GABA agonists , since these are prone to resulting in a natural response of the body reducing the amount of targeted GABA receptors (via a process called down-regulation); the result would include withdrawal.
A more strategic & sustainable approach would be to use substances which act in a more sustainable way, such as Positive Allosteric Modulator's (PAM) or perhaps a GABA transaminase inhibitor. (Inhibiting the GABA transaminase enzymes reduces the degradation of GABA, leading to increased GABA concentrations). Maybe constant use of this type of inhibitor might also cause similar withdrawal issues in the long-term...

Other options include Kava, an enjoyable & unique botanical which upregulates GABA, and Magnolia Bark, which potentiates GABA & has therapeutic cannabinoid properties.

Sorry, loose in my phrasing. Wasn’t suggesting synthetic GABA.

Good lists by the way. Suppose things like magnesium threonate and theanine would also get in there. And, of course, long-term meditative practices have proven potent in this regard.

On allopregnanolone as a GABA PAM, an interesting quirk I noted in another thread: there’s the possibility of potentiating the stress response with neurosteroids and the related GABA increase.

In brief, there are indications that stress can cause dephosphorylation of the KCC2 co-transporter resulting in the collapse of the chloride gradient. Consequently, GABA can end up causing depolarisation of GABAergic neurons, thus potentiating the stress response and elevating CRH.

Here’s a couple of quick references:
The reciprocal regulation of stress hormones and GABAA receptors
Chronic stress shifts the GABA reversal potential in the hippocampus and increases seizure susceptibility

A collapse of the chloride gradient could be one reason why some people report adverse effects/feel significantly more anxious on pregnenolone.

Honestly, I’m cautious on the subject of direct hormone supplementation, even precursors like PREG. Think, at least, prolactin and saliva hormone testing beforehand would be wise. Clearly we understand basic steroid synthesis on paper but people do seem to react in counterintuitive ways, which is suggestive of further nuance. Be interesting to see how knowledge evolves on this.

BTW, interesting note on olive oil - I had forgotten about its high squalene content.

 

[bdawg]

Agmatine increases cAMP levels, which activates PPAR-alpha & PGC1-alpha, thus directly stimulating Allopregnanolone.
PDE4 inhibitor's raise cAMP levels, and would also stimulate Allopregnanolone production.
(forskolin, luteolin, artichoke extract & caffeine all raise cAMP levels - forskolin directly, the rest are PDE4i's)

re Agmatine:
Our previous investigation indicates that Agmatine increases cellular [cAMP] (3, 6).
This finding led to the hypothesis that Agmatine may have a widespread influence on whole body metabolic profiling by elevating the intracellular cAMP level.
One of the many metabolic functions known to be impacted by cAMP signaling is the activation of gene expression and its action on both the peroxisomal proliferator-activated receptor-α (PPARα) and its coactivator, PGC1α.

Another way to raise cAMP levels is using a PDE4 inhibitor.

Coleus Forskohlii activates the enzyme adenylyl cyclase which then increases intracellular levels of cAMP.

More insight on Agmatine (from my main thread on it)
- The molecular and metabolic influence of long-term Agmatine consumption -
Subsequently, Agmatine induced a widespread impact on gene expression and metabolic profiling, including: (a) activation of PPARα, and its coactivator PGC1α; (b) increased expression of PPARγ and genes regulating thermogenesis, gluconeogenesis, and carnitine (Car) biosynthesis and transport.
________________________
Paper PDE4 enzyme & role
PDE4 as a target for cognition enhancement

Incidentally, increasing cAMP levels, and reducing PDE4 will [temporarily] counter-act sleep-deprivation symptoms:

does this mean agmatine opposes mildronate in terms of enhancing cartinine and fatty acid synthesis?

 

[Sativa]

It seems DHEA also activates PPAR-alpha:

Dehydroepiandrosterone (DHEA), the major precursor of androgens and estrogens, has several beneficial effects on the immune system, on memory function, and in modulating the effects of diabetes, obesity, and chemical carcinogenesis.
Treatment of rats with DHEA influences expression of cytochrome P450 (P450) genes, including peroxisome proliferator-activated receptor alpha (PPAR alpha)- and pregnane X receptor (PXR)-mediated induction of CYP4As and CYP3A23
...

The effect of DHEA on the activation of the xenosensors PPAR alpha, PXR

 

[Sativa]

Many thanks for the info on PEA and agmatine, both had completely passed me by.

Check out my main thread on Agmatine
Agmatine - A 'Peaty' Substance With Potential?

 

[Sativa]

More juicy insight into progesterone's properties. They are probably good one's to mimic with other natural substances etc...

Progesterone, through its neurosteroid active metabolites (5α-dihydroP & alloP) acts indirectly as a positive allosteric modulator of the GABAAreceptor.
...as agonists of the pregnane X receptor (PXR), albeit weakly so (EC50 >10 µM).
...progesterone induces several P450 enzymes such as CYP3A4

...our data describe that Progesterone elicits an increase in BDNF release from glia via a Pgrmc1-induced ERK5 signaling mechanism and identify Pgrmc1 as a potential therapeutic target for future hormone-based drug development for the treatment of such degenerative diseases as Alzheimer's disease as well as other diseases wherein neurotrophin dysregulation is noted.

So, several routes to both stimulate endogenous AlloP synthesis and mimic/recreate a custom selection of Progesterones properties...

Stimulate endogenous synthesis:
PPARa, PGC-1a
'mimic' Progesterone:
GABA(a) PAM, PXR activator, BDNF, etc...

Insight re inhibitors & inducers of CYP3A4 (a common target/enzyme) herbpedia.wikidot.com/cyp3a4

Palmitoylethanolamide inducing 5α-reductase A potential anti-finasteride 'remedy solution'?
possibly via the AlloP, or an indirect effect of PEA's wide range of Cannabinoid system properties, including the GPR55 receptor...

...interestingly, the effect of PEA was partially inhibited by finasteride, a 5α-reductase inhibitor.

more relevant bits from the paper:
A similar profile of activity was demonstrated by ALLO and the lack of an additive effect with PEA suggests that the reduction of oxidative stress by PEA is mediated through ALLO synthesis.

The present study provides evidence indicating the involvement of the saturated acylethanolamide PEA in ALLO synthesis through PPAR-α in astrocytes and explores the antioxidative activity of this molecule, confirming its homeostatic and protective role both under physiological and pathological conditions.

 

[Sativa]

on BDNF (ps. estrogen reduces it's efficacy)

...estrogen and BDNF are antagonistic to each other as animals exposed to estrogen cannot remember very well. BDNF is akin to an anabolic steroid for the brain, and estrogen powerfully impairs its effects, especially in cases of traumatic brain injury of radiation exposure. The studies with rodents found that exposure to estrogen gave the rodents a form of dementia not unlike Alzheimer disease (AD) in humans.
Now this study finally replicates the findings in humans

... BDNF expression is significantly enhanced by environmental enrichment and appears to be the primary source of environmental enrichments ability to enhance cognitive processes. Environmental enrichment enhances synaptogenesis, dendridogenesis, and neurogenesis, leading to improved performance on various learning and memory tasks. BDNF mediates more pathways involved in these enrichment-induced processes than any other molecule...

More on Progesterone's properties, PXR activator; stimulates Thyroid; counters cortisol/stress (anti-cortisol)

Pregnenolone is an activator of the so-called Pregnane X Receptor (PXR). Activators of this receptor has been shown to stimulate the excretion of toxic substances and lower cholesterol. ...Pregnenolone is catatoxic, and if there is a lot of junk in your liver or somewhere else initially you may get this reaction that looks like cortisol but is in fact part of the detoxification process.

Progesterone stimulates the thyroid, but so does DHEA (in smaller doses only).
...As Peat said cortisol inactivates T3 and inhibits synthesis of T4. So cortisol is antagonistic to thyroid function (more or less). If pregnenolone is indeed a cortisol antagonist then it is probably acting directly itself on thyroid.
...The pregnenolone could have also stimulated the conversion of T4 into T3, or (more likely) triggered conversion of cholesterol into downstream steroids.

From the compounds tested, clove and thyme extracts as well as curcumin activated the PXR.

curcumin - cheap, abundant, fat soluble, anti-stress & activates PXR (also cannabinoid & MAOI properties)

Mimicking Progesterone further - anti-cortisol; anti-estrogen; pro-anabolic / anti-catabolic...

Progesterone would be my choice for a GR antagonist as per my thread on its antagonism to GR (The Anti-cortisol Mechanism Of Progesterone). In addition, as I posted in another thread, progesterone has proven anabolic effects at least in animal studies (The Anabolic Effects Of Progesterone). Needless to say, Peat has also written a ton on progesterone, of its opposition to cortisol and estrogen, and its role in protecting from tissue destruction.

All anti-cortisol (aka anti-glucocorticoid) & all anti-estrogenic substances are anabolic/anti-catabolic
eg: Vitamin E, Salicylic acid, Magnesium, Curcumin (anti-glucocorticoid/anti-cortisol)