Allopregnanolone May Soon Be Approved As A Fast-acting Antidepressant

[broozer]

Yes, and that is what I am doing with zoloft currently, until I can get some mirtazapine. I take about 6 mg (the doctor prescribed 25mg which is pretty much the lowest dose because they assume it's for serotonin reuptake inhibition/"anti-depressant"! lol) Anyways, it's been fine. In fact, the research shows that the purpose of low dose ssri is to avoid the sleepiness of progesterone supplementation.

thats awesome, at what time do you take it ? can u like instantly feel the allo rasing? i got the 10mg version prescribed today :)

 

[alywest]

thats awesome, at what time do you take it ? can u like instantly feel the allo rasing? i got the 10mg version prescribed today :)

Of zoloft? I didn't realize they even had that low of a dose! LOL If it's fluoxetine you'd only want to take about 2mg but if it's zoloft that would translate to roughly 6mg. I think if you just cut your in half it would be fine. I doubt the 1mg would make a huge difference. Or just slice it with a small, sharp knife to slightly over half. If I even take 10mg I get serotonin symptoms, like clenched jaw. I don't feel the allo rising, but I take it in the morning and I notice after a while that I haven't been as irritable! If I'm really irritable I realize that I need to take it still. It's not going to be like taking something that makes you feel high like xanax. It's a lot more like you just aren't as easily bothered. And interestingly the effects are almost immediate whereas the "anti-depressant" effects of SSRI's are supposed to take a long time (2-4 weeks at the low end.) I still take progesterone during my luteal phase as I'm so estrogen dominant I still need it, even though this is supposed to take it's place. I've also been taking myo-inositol and d chiro-inositol which have been shown to increase progesterone levels over time. I just started those but I have already noticed my blood sugar seems a lot more stable. So I don't feel those dips in blood sugar like I usually do. It's supposed to increase insulin sensitivity. Also PEA (palmitoylethanolamide, with luteolin in mirica) has been really good for me. The combo of all three seem to be making me a lot more cheerful. I also take other things but those three are good for the mood.

 

[broozer]

yes it is actually fluoxetine. ill give it a go, 2,5mg seems doable in an exact way, maybe even 1,25mg. would resolving it in water to dose more exactly lead to shenanigans with pharmacokinetics?

 

[alywest]

yes it is actually fluoxetine. ill give it a go, 2,5mg seems doable in an exact way, maybe even 1,25mg. would resolving it in water to dose more exactly lead to shenanigans with pharmacokinetics?

It also depends on your weight, so if you're 150 lb, you should aim for 2mg. It is based on weight in the rat studies so you do have to take enough, but you also don't want too much! I wouldn't do the water thing just because the pills taste so absolutely disgusting. I think if you cut yours into 1/4 you should have no problem. That's what I do and it works perfect.

 

[broozer]

thanks for the advise! last year i was like 72kg @12%,smoker and shredded. but now im rather 75 @ 18%, is this important?
kind regards from europe!

 

[LeeLemonoil]

I think 3b-anediol is even more effective or important in normalizing affective disorders, especially in males, though allo is viable as well

 

[broozer]

I think 3b-anediol is even more effective or important in normalizing affective disorders, especially in males, though allo is viable as well

interesting,i never heard of it! how to increase this one? sounds like a cannabinoid :)

 

[LeeLemonoil]

It's not a cannabinoid but an androgen - one of it actions is involved in healthy endogenous opiode metabolism/regulation in fact, but that's not the sole reason why this steroid is so crucial to mental health

 

[LeeLemonoil]

Neurosteroid metabolites of testosterone and progesterone differentially inhibit ERK phosphorylation induced by amyloid β in SH-SY5Y cells and prim... - PubMed - NCBI

Neurosteroid metabolites of testosterone and progesterone differentially inhibit ERK phosphorylation induced by amyloid β in SH-SY5Y cells and primary cortical neurons.
Mendell AL1, Chung BYT1, Creighton CE1, Kalisch BE1, Bailey CDC1, MacLusky NJ2.
Author information
Abstract
Gonadal steroid hormones exert neurotrophic and neuroprotective effects on the brain. Recent work suggests potential neuroprotective roles for the 3α-hydroxy, 5α-reduced metabolites of these hormones. Two such metabolites are 5α-androstane-3α,17β-diol (3α-diol) and 5α-pregnan-3α-ol-20-one (allopregnanolone; Allo), which may contribute to the overall protection conferred by their precursors (testosterone and progesterone, respectively) through mechanisms including potentiation of gamma-aminobutyric acid (GABA)A receptor (GABAAR) activity. We have previously demonstrated that physiological concentrations of 3α-diol inhibit prolonged phosphorylation of extracellular signal-regulated kinase (ERK) and the associated neurotoxicity resulting from amyloid β peptide 1-42 (Aβ42) exposure in vitro. In the present study, we sought to characterize the GABAAR-dependency of 3α-diol's effects, compared to those of Allo, in SH-SY5Y human female neuroblastoma cells and primary cortical neurons isolated from postnatal day 0-1 mice. Both 3α-diol and Allo prevented Aβ42-mediated ERK phosphorylation in SH-SY5Y cells, with substantially different concentration requirements (10 nM for 3α-diol, 100 nM for Allo). Pharmacological inhibition of GABAAR with picrotoxin did not prevent this effect, indicating that neurosteroid-mediated ERK inhibition in SH-SY5Y cells may be GABAAR-independent. While 10 nM and 100 nM concentrations of both neurosteroids inhibited ERK phosphorylation induced by Aβ42 in primary cortical neurons, which have high expression levels of GABAARs, only the effects of Allo were significantly inhibited by picrotoxin. These results suggest that neurosteroid metabolites of testosterone and progesterone may contribute to neuroprotection by suppressing ERK phosphorylation through both GABAAR-dependent and -independent mechanisms.

 

[LeeLemonoil]

5α-Reduced neurosteroids sex-dependently reverse central prenatal programming of neuroendocrine stress responses in rats. - PubMed - NCBI

5α-Reduced neurosteroids sex-dependently reverse central prenatal programming of neuroendocrine stress responses in rats.

Abstract
Maternal social stress during late pregnancy programs hypothalamo-pituitary-adrenal (HPA) axis hyper-responsiveness to stressors, such that adult prenatally stressed (PNS) offspring display exaggerated HPA axis responses to a physical stressor (systemic interleukin-1β; IL-1β) in adulthood, compared with controls. IL-1β acts via a noradrenergic relay from the nucleus tractus solitarii (NTS) to corticotropin releasing hormone neurons in the paraventricular nucleus (PVN). Neurosteroids can reduce HPA axis responses, so allopregnanolone and 3β-androstanediol (3β-diol; 5α-reduced metabolites of progesterone and testosterone, respectively) were given subacutely (over 24 h) to PNS rats to seek reversal of the "programmed" hyper-responsive HPA phenotype. Allopregnanolone attenuated ACTH responses to IL-1β (500 ng/kg, i.v.) in PNS females, but not in PNS males. However, 3β-diol normalized HPA axis responses to IL-1β in PNS males. Impaired testosterone and progesterone metabolism or increased secretion in PNS rats was indicated by greater plasma testosterone and progesterone concentrations in male and female PNS rats, respectively. Deficits in central neurosteroid production were indicated by reduced 5α-reductase mRNA levels in both male and female PNS offspring in the NTS, and in the PVN in males. In PNS females, adenovirus-mediated gene transfer was used to upregulate expression of 5α-reductase and 3α-hydroxysteroid dehydrogenase mRNAs in the NTS, and this normalized hyperactive HPA axis responses to IL-1β. Thus, downregulation of neurosteroid production in the brain may underlie HPA axis hyper-responsiveness in prenatally programmed offspring, and administration of 5α-reduced steroids acutely to PNS rats overrides programming of hyperactive HPA axis responses to immune challenge in a sex-dependent manner.

 

[broozer]

It also depends on your weight, so if you're 150 lb, you should aim for 2mg. It is based on weight in the rat studies so you do have to take enough, but you also don't want too much! I wouldn't do the water thing just because the pills taste so absolutely disgusting. I think if you cut yours into 1/4 you should have no problem. That's what I do and it works perfect.

i started today with 2mg. i felt more social, but still anxios. lets see how sleep is. the half live of fluox is 6-7 days. so, to avoid strong accumulative effects should i just take 2mg once or twice a week?
@LeeLemonoil thanks, prenatal stress...ur study perfectly named it.

 

[alywest]

5α-Reduced neurosteroids sex-dependently reverse central prenatal programming of neuroendocrine stress responses in rats. - PubMed - NCBI

5α-Reduced neurosteroids sex-dependently reverse central prenatal programming of neuroendocrine stress responses in rats.

Abstract
Maternal social stress during late pregnancy programs hypothalamo-pituitary-adrenal (HPA) axis hyper-responsiveness to stressors, such that adult prenatally stressed (PNS) offspring display exaggerated HPA axis responses to a physical stressor (systemic interleukin-1β; IL-1β) in adulthood, compared with controls. IL-1β acts via a noradrenergic relay from the nucleus tractus solitarii (NTS) to corticotropin releasing hormone neurons in the paraventricular nucleus (PVN). Neurosteroids can reduce HPA axis responses, so allopregnanolone and 3β-androstanediol (3β-diol; 5α-reduced metabolites of progesterone and testosterone, respectively) were given subacutely (over 24 h) to PNS rats to seek reversal of the "programmed" hyper-responsive HPA phenotype. Allopregnanolone attenuated ACTH responses to IL-1β (500 ng/kg, i.v.) in PNS females, but not in PNS males. However, 3β-diol normalized HPA axis responses to IL-1β in PNS males. Impaired testosterone and progesterone metabolism or increased secretion in PNS rats was indicated by greater plasma testosterone and progesterone concentrations in male and female PNS rats, respectively. Deficits in central neurosteroid production were indicated by reduced 5α-reductase mRNA levels in both male and female PNS offspring in the NTS, and in the PVN in males. In PNS females, adenovirus-mediated gene transfer was used to upregulate expression of 5α-reductase and 3α-hydroxysteroid dehydrogenase mRNAs in the NTS, and this normalized hyperactive HPA axis responses to IL-1β. Thus, downregulation of neurosteroid production in the brain may underlie HPA axis hyper-responsiveness in prenatally programmed offspring, and administration of 5α-reduced steroids acutely to PNS rats overrides programming of hyperactive HPA axis responses to immune challenge in a sex-dependent manner.

That's interesting about elevated plasma testosterone and progesterone in male and female rats, respectively. That's what I've been experiencing, I think, when I take progesterone without the low dose SSRI, it just doesn't do anything. I don't believe I had low progesterone in my system when I was pregnant, either, even though I didn't take supplements, because both of my children were carried to term, yet I have clear estrogen dominance symptoms. I'm not sure I understand if there's a particular supplement that can increase 5a-reduced neurosteroid production. Sorry in advance if that's a stupid question~

 

[broozer]

okay.the sleep after 2mg fluoxetine didnt feel any better. to get the 3b-diol working i should have enough DHEA or DHT, right?

3β-Androstanediol - Wikipedia

i have midrange-high DHEA. DHT is low-mid, but im in status post finasteridum..so its difficult.some ways to boost those enzymes for the conversion?

 

[alywest]

okay.the sleep after 2mg fluoxetine didnt feel any better. to get the 3b-diol working i should have enough DHEA or DHT, right?

3β-Androstanediol - Wikipedia

i have midrange-high DHEA. DHT is low-mid, but im in status post finasteridum..so its difficult.some ways to boost those enzymes for the conversion?

Biomarkers for PTSD at the Interface of the Endocannabinoid and Neurosteroid Axis :

compelling evidence indicates stimulation of the intracellular endocannabinoid target, peroxisome-proliferator activated receptor (PPAR)-α by its endogenous neuromodulator, N-palmitoylethanolamine (PEA) engages the biosynthesis of neurosteroids to modulate emotional behavior (Locci and Pinna, 2017b; Locci et al., 2018)

Given that endoannabinoids activate PPAR-α (Marsicano et al., 2002; Pistis and Melis, 2010), the activation of these nuclear receptors represents a novel mechanism by which cannabinoids may modulate behavior. The endocannabinoid congener, N-palmitoylethanolamine (PEA) is a PPAR-α endogenous agonist, which is decreased in PTSD patients (Wilker et al., 2016). Recent preclinical findings showed that supplementing PEA in rodent PTSD models improves emotional behavior by enhancing allopregnanolone biosynthesis in corticolimbic glutamatergic neurons.

I obtained PEA from amazon, I don't know if you can get it that way where you are, but it is manufactured in the Netherlands so perhaps it's readily available there as well:

https://www.amazon.com/MiricaTM-Pal...ds-Anti-Inflammatory-Supplement/dp/B07365MZLY

This in combination with the SSRI should help quite a bit. It is a bit pricey, but it has been very helpful to me.

 

[Blossom]

Biomarkers for PTSD at the Interface of the Endocannabinoid and Neurosteroid Axis :

compelling evidence indicates stimulation of the intracellular endocannabinoid target, peroxisome-proliferator activated receptor (PPAR)-α by its endogenous neuromodulator, N-palmitoylethanolamine (PEA) engages the biosynthesis of neurosteroids to modulate emotional behavior (Locci and Pinna, 2017b; Locci et al., 2018)

Given that endoannabinoids activate PPAR-α (Marsicano et al., 2002; Pistis and Melis, 2010), the activation of these nuclear receptors represents a novel mechanism by which cannabinoids may modulate behavior. The endocannabinoid congener, N-palmitoylethanolamine (PEA) is a PPAR-α endogenous agonist, which is decreased in PTSD patients (Wilker et al., 2016). Recent preclinical findings showed that supplementing PEA in rodent PTSD models improves emotional behavior by enhancing allopregnanolone biosynthesis in corticolimbic glutamatergic neurons.

I obtained PEA from amazon, I don't know if you can get it that way where you are, but it is manufactured in the Netherlands so perhaps it's readily available there as well:

https://www.amazon.com/MiricaTM-Pal...ds-Anti-Inflammatory-Supplement/dp/B07365MZLY

This in combination with the SSRI should help quite a bit. It is a bit pricey, but it has been very helpful to me.

Thanks @alywest.

 

[broozer]

Biomarkers for PTSD at the Interface of the Endocannabinoid and Neurosteroid Axis :

compelling evidence indicates stimulation of the intracellular endocannabinoid target, peroxisome-proliferator activated receptor (PPAR)-α by its endogenous neuromodulator, N-palmitoylethanolamine (PEA) engages the biosynthesis of neurosteroids to modulate emotional behavior (Locci and Pinna, 2017b; Locci et al., 2018)

Given that endoannabinoids activate PPAR-α (Marsicano et al., 2002; Pistis and Melis, 2010), the activation of these nuclear receptors represents a novel mechanism by which cannabinoids may modulate behavior. The endocannabinoid congener, N-palmitoylethanolamine (PEA) is a PPAR-α endogenous agonist, which is decreased in PTSD patients (Wilker et al., 2016). Recent preclinical findings showed that supplementing PEA in rodent PTSD models improves emotional behavior by enhancing allopregnanolone biosynthesis in corticolimbic glutamatergic neurons.

I obtained PEA from amazon, I don't know if you can get it that way where you are, but it is manufactured in the Netherlands so perhaps it's readily available there as well:

https://www.amazon.com/MiricaTM-Pal...ds-Anti-Inflammatory-Supplement/dp/B07365MZLY

This in combination with the SSRI should help quite a bit. It is a bit pricey, but it has been very helpful to me.

thank you ,i might try.i take so many supplements already. ashvaganda, passiflora,melatonin. can i combine all those?next on my list would be high dose niacinamide.

 

[LeeLemonoil]

@boozer

Tianeptine might do a lot of good

Effects of Tianeptine on Adult Rats Following Prenatal Stress.
Lee H, et al. Clin Psychopharmacol Neurosci. 2018.
Show full citation
Abstract
Objective: Exposing a pregnant female to stress during the critical period of embryonic fetal brain development increases the risk of psychiatric disorders in the offspring. The objective of this study was to investigate the effect of antidepressant tianeptine on prenatally stressed (PNS) rats.

Methods: In this study, a repeated variable stress paradigm was applied to pregnant rats during the last week of gestation. To investigate the effects of antidepressant tianeptine on PNS rats, behavioral and protein expression analyses were performed. Forced swim test, open field test, and social interaction test were performed to determine changes in PNS rats compared to non-stressed offspring. Haloperidol was used as a positive control as an antipsychotic drug based on previous studies.

Results: Behavioral changes were restored after treatment with tianeptine or haloperidol. Western blot and immunohistochemical analyses of the prefrontal cortex revealed downregulation of several neurodevelopmental proteins in PNS rats. After treatment with tianeptine or haloperidol, their expression levels were increased.

Conclusion: Downregulation of several proteins in PNS rats might have caused subsequent behavioral changes in PNS rats. After tianeptine or haloperidol treatment, behavioral changes in PNS rats were restored. Therefore, tianeptine might decrease incidence of prenatal stress related-psychiatric disorders such as depression and schizophrenia.

PMID
29739134 []
PMCID
PMC5953020

 

[alywest]

@boozer

Tianeptine might do a lot of good

Effects of Tianeptine on Adult Rats Following Prenatal Stress.
Lee H, et al. Clin Psychopharmacol Neurosci. 2018.
Show full citation
Abstract
Objective: Exposing a pregnant female to stress during the critical period of embryonic fetal brain development increases the risk of psychiatric disorders in the offspring. The objective of this study was to investigate the effect of antidepressant tianeptine on prenatally stressed (PNS) rats.

Methods: In this study, a repeated variable stress paradigm was applied to pregnant rats during the last week of gestation. To investigate the effects of antidepressant tianeptine on PNS rats, behavioral and protein expression analyses were performed. Forced swim test, open field test, and social interaction test were performed to determine changes in PNS rats compared to non-stressed offspring. Haloperidol was used as a positive control as an antipsychotic drug based on previous studies.

Results: Behavioral changes were restored after treatment with tianeptine or haloperidol. Western blot and immunohistochemical analyses of the prefrontal cortex revealed downregulation of several neurodevelopmental proteins in PNS rats. After treatment with tianeptine or haloperidol, their expression levels were increased.

Conclusion: Downregulation of several proteins in PNS rats might have caused subsequent behavioral changes in PNS rats. After tianeptine or haloperidol treatment, behavioral changes in PNS rats were restored. Therefore, tianeptine might decrease incidence of prenatal stress related-psychiatric disorders such as depression and schizophrenia.

PMID
29739134 []
PMCID
PMC5953020

It's my understanding that tianeptine is a serotonin reuptake enhancer, whereas lisuride agonizes and antagonizes various receptors. What would you say is the major difference in their mechanisms of action? Why would one be better than the other? Also, it seems like it's really difficult to source tianeptine. It's not even technically legal in the states, is it?

 

[LeeLemonoil]

Sorry @alywest, I always forget Tia is not for prescription in the US. The MoA has been described in various threads here though. NMDA-Antagonism is imo the crucial effect of Tia in contrast to many other anti-depressives.

Topic:
Maybe it is not Allopreg but its Sulfate that is more important for mood regulation, at least this very handy research hints in that direction. Any idea how and if Sulfated steroids get into the brain and work there?

http://www.biomed.cas.cz/physiolres/pdf/64 Suppl 2/64_S275.pdf

 

[alywest]

Sorry @alywest, I always forget Tia is not for prescription in the US. The MoA has been described in various threads here though. NMDA-Antagonism is imo the crucial effect of Tia in contrast to many other anti-depressives.

Topic:
Maybe it is not Allopreg but its Sulfate that is more important for mood regulation, at least this very handy research hints in that direction. Any idea how and if Sulfated steroids get into the brain and work there?

http://www.biomed.cas.cz/physiolres/pdf/64 Suppl 2/64_S275.pdf

It sounds like in the case with DHEA, if it's applied topically, it avoids the sulfation process in the liver, but that is the only form that is able to cross the blood-brain barrier and once in the brain it's immediately transformed to DHEA-S. DHEA taken orally, however, is sulfated during its pass through the liver, but then is unable to cross the blood-brain barrier. So it will increase your DHEA-S test results for blood, urine, saliva, but that is not going to be able to tell you how much you have in your brain.

From the study you linked:
Considering the role of steroid sulfates in the brain it is necessary to take into account that we measured circulating steroid levels in blood, which do not necessarily correspond to levels in the brain or even in its specific regions. Sulfates have a limited ability to cross the blood-brain barrier, and the activity of sulfotransferase in the brain, which is responsible for the sulfatation of steroids, is very low (Kříž et al. 2005). Generally, sulfates and conjugates of steroids in are higher in plasma than free steroids. Despite this, the ratio of free and conjugated or sulfatated steroids is an important feature of the steroid metabolome, and it could be reflected in various target regions in the brain. In addition, levels of selected steroids in the plasma or serum could be helpful as markers of psychiatric disorders.

So it sounds like the study reflected serum levels and that was what showed the most benefit for men, so perhaps taking steroids orally is more useful if the sulfated form is what you're after. I don't totally understand why sulfated would be more beneficial, and personally I think DHEA is better topically because I would rather raise brain levels. But I'm not a dude.