How Can I Downregulate Glucocorticoid Receptors (PSSD Theory)?

[Lokzo]

So it is known that SSRI downregulate CRF receptor density, thus ACTH falls and GR gets overexpressed.


This could explain why people feel better on CORTISOL supplement plus serotonin agonist. At the same time.
And also explains why people feel like ***t on cyproheptadine and cured on withdrawal (me, 3-4 days later).
Since cyproheptadine upregulates CRF receptor and serotonin receptor at the same time.

I am basically looking for a way to replicate what Cyproheptadine does to me when it "wears off" - that is when I feel cured. I am starting to strongly believe this is cortisol/GR expression mediated.

GR appears to repress 5-HT1A autoreceptors [96]. Glucocorticoids can also uncouple 5-HT1A autoreceptors by reducing GIRK2 RNA levels [29]. Paradoxically, over-expression of MR or GR in the mouse forebrain increases 5-HT1A heteroreceptor expression (possibly via suppression of glucocorticoids), which was associated with an anti-anxiety/anti-depressed phenotype and increased SSRI responsiveness, respectively [97,98].

"GR also regulates 5HT1A expression. SSRI's have been observed to increase GR expression. It could be the case that your GR's are overexpressed (IE too many receptors), causing you to be too sensitive to cortisol and a negative feedback that lowers cortisol and improperly regulates 5HT1A. Then when you get majorly sick, cortisol spikes and downregulates GR, returning you to a more normal level of receptors. But for some reason it does not last."

Any ideas are VERY welcomed.

Here's a snapshot of my Cortisol levels:

 

[olive]

A component of red ginseng is a glucocorticoid antagonist:
Glucocorticoid receptor agonist compound K regulates Dectin-1-dependent inflammatory signaling through inhibition of reactive oxygen species. - PubMed - NCBI

Otherwise focusing on lowering inflammatory cytokines and hence prostaglandins may be helpful: olive leaf extract, y-gamma vitamin e, taurine, glycine, agmatine, l-threonine + pau d’arco, chamomile, green tea, etc.

It’s also worth noting AAS powerfully supress cortisol, but this comes with other side effects.

 

[Hans]

So it is known that SSRI downregulate CRF receptor density, thus ACTH falls and GR gets overexpressed.


This could explain why people feel better on CORTISOL supplement plus serotonin agonist. At the same time.
And also explains why people feel like ***t on cyproheptadine and cured on withdrawal (me, 3-4 days later).
Since cyproheptadine upregulates CRF receptor and serotonin receptor at the same time.

I am basically looking for a way to replicate what Cyproheptadine does to me when it "wears off" - that is when I feel cured. I am starting to strongly believe this is cortisol/GR expression mediated.

GR appears to repress 5-HT1A autoreceptors [96]. Glucocorticoids can also uncouple 5-HT1A autoreceptors by reducing GIRK2 RNA levels [29]. Paradoxically, over-expression of MR or GR in the mouse forebrain increases 5-HT1A heteroreceptor expression (possibly via suppression of glucocorticoids), which was associated with an anti-anxiety/anti-depressed phenotype and increased SSRI responsiveness, respectively [97,98].

"GR also regulates 5HT1A expression. SSRI's have been observed to increase GR expression. It could be the case that your GR's are overexpressed (IE too many receptors), causing you to be too sensitive to cortisol and a negative feedback that lowers cortisol and improperly regulates 5HT1A. Then when you get majorly sick, cortisol spikes and downregulates GR, returning you to a more normal level of receptors. But for some reason it does not last."

Any ideas are VERY welcomed.

Here's a snapshot of my Cortisol levels:
View attachment 13501

What is the individual numbers of the salivary cortisol test?

Your cortisol is more on the high side than the low side according to the saliva test. Cortisol can downregulate its own receptor thus leaving you with high cortisol and also high CRH and ACTH.

If you think you have low cortisol, it would only be natural for the receptors to increase their sensitivity. You don't want low cortisol and low receptor sensitivity.

DHEA inhibits nuclear cortisol receptor translocation. Vit D also helps to block the cortisol receptor. Progesterone and 6-keto P can also block the cortisol receptor.

Have you had your DHEA-S tested?

 

[lampofred]

Red light maybe? Chronic darkness powerfully increases cortisol.

 

[Lokzo]

A component of red ginseng is a glucocorticoid antagonist:
Glucocorticoid receptor agonist compound K regulates Dectin-1-dependent inflammatory signaling through inhibition of reactive oxygen species. - PubMed - NCBI

Otherwise focusing on lowering inflammatory cytokines and hence prostaglandins may be helpful: olive leaf extract, y-gamma vitamin e, taurine, glycine, agmatine, l-threonine + pau d’arco, chamomile, green tea, etc.

It’s also worth noting AAS powerfully supress cortisol, but this comes with other side effects.

I might have to retry Ginseng again. But, its usually so warming and anxiety-inducing for me. Feels overstimulating.

I really do like Olive leaf extract. Taurine as well. Thanks for pointers man.

 

[Lokzo]

What is the individual numbers of the salivary cortisol test?

Your cortisol is more on the high side than the low side according to the saliva test. Cortisol can downregulate its own receptor thus leaving you with high cortisol and also high CRH and ACTH.

If you think you have low cortisol, it would only be natural for the receptors to increase their sensitivity. You don't want low cortisol and low receptor sensitivity.

DHEA inhibits nuclear cortisol receptor translocation. Vit D also helps to block the cortisol receptor. Progesterone and 6-keto P can also block the cortisol receptor.

Have you had your DHEA-S tested?

Hey Hans, Thanks for the response brother. Well, I usually wake up with enough energy to get moving and train, all without caffeine. I am just stumped as to why/how Cyproheptadine 'cures' me 3-4 days later.

What I experience during this window of cure:
-Better pumps in the gym
-Strength and muscle contractility improved
-Vibrational sensation feeling
-Musical appreciation enhanced
-Outstanding libido (Elimination of my fkn default NUMB genitals/PSSD).

 

[Hans]

Hey Hans, Thanks for the response brother. Well, I usually wake up with enough energy to get moving and train, all without caffeine. I am just stumped as to why/how Cyproheptadine 'cures' me 3-4 days later.

What I experience during this window of cure:
-Better pumps in the gym
-Strength and muscle contractility improved
-Vibrational sensation feeling
-Musical appreciation enhanced
-Outstanding libido (Elimination of my fkn default NUMB genitals/PSSD).


View attachment 13509

Maybe you can just continue with taking cypro for a day or two and then take of for 2-4 days and see if you get progressively better.

 

[Lokzo]

Maybe you can just continue with taking cypro for a day or two and then take of for 2-4 days and see if you get progressively better.

I mean that's literally all I'm left with now. Thankfully Cypro is working it's magic for me. The plan is to need Cypro less and less over time.
I also notice when I'm "cured"
-Pumps are engorging again
-Hot water I can actually feel that cosy feeling on the skin again, like endorphin release or something.
-Music sounds better.

So bizzare.

 

[Hans]

I mean that's literally all I'm left with now. Thankfully Cypro is working it's magic for me. The plan is to need Cypro less and less over time.
I also notice when I'm "cured"
-Pumps are engorging again
-Hot water I can actually feel that cosy feeling on the skin again, like endorphin release or something.
-Music sounds better.

So bizzare.

If your metabolized cortisol is low, it points to low 5alpha reductase activity in the liver and/or fatty liver or lastly kidney problems where you're not excreting the cortisol metabolites, but rather reactivating them.

 

[Lokzo]

If your metabolized cortisol is low, it points to low 5alpha reductase activity in the liver and/or fatty liver or lastly kidney problems where you're not excreting the cortisol metabolites, but rather reactivating them.

Ahhh interesting. Thanks.

Also, do you know the potential mechanism as to how cyproheptadine affects heart function? I know some users experience chest pain. I have noticed very minor chest pain today. Is this serotonin-related? Calcium channel blocking activity?

 

[Lokzo]

@Hans
The last few days I have been using Licorice, and it seems to mimic what Cyproheptadine does to me on the withdrawal.

I feel amazing on it. Pumps back in the gym, feelings back, PSSD symptoms gone.

So my question is, how can I bring up aldosterone/cortisol without needing this estrogenic herb.

 

[deliciousfruit]

Strange, I have PSSD but feel great on cyproheptadine. In fact, I've never been able to witness what happens after 4 days because I've always had to continuously take it to not feel completely crap. The first few times taking it I had a huge surge in libido too.

 

[Lokzo]

Strange, I have PSSD but feel great on cyproheptadine. In fact, I've never been able to witness what happens after 4 days because I've always had to continuously take it to not feel completely crap. The first few times taking it I had a huge surge in libido too.

Super fascinating!

What triggered your PSSD?

What dosage are you using of the cypro?

How have you not been eating like a mad man!?!? That stuff makes me insanely hungry haha.

 

[deliciousfruit]

Super fascinating!

What triggered your PSSD?

What dosage are you using of the cypro?

How have you not been eating like a mad man!?!? That stuff makes me insanely hungry haha.

Zoloft.
1mg in the morning and 1mg before bed.
It doesn't increase my appetite at all sadly, I really struggle to get in enough calories daily.