An Excellent Explaination of How SSRI's Inhibit Sert

This is a place to post research you have done on the topic along with your conclusions.
Tree
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Re: An Excellent Explaination of How SSRI's Inhibit Sert

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Pssd suffers from France should try to contact the author. She seems to be knowledgeable of how ssri's affect the serotonin transporter. It would be interesting to know if she has any updated information, aware of pssd, and opinions on it.

https://t3s-1124.biomedicale.parisdesca ... ne-baudry/
Tree
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Re: An Excellent Explaination of How SSRI's Inhibit Sert

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"This leaves us with the following model for a novel mechanism of action for SSRIs:
1) SSRIs suppress WNT signaling in the raphe leading to a maturation of miR-16. This causes an increase in expression of S100beta and a decrease in SERT expression in these 5HT neurons".
2) SSRIs increase S100beta release in the locus ceruleus causing a decrease in miR-16 expression in these NE neurons. That decrease in miR-16 expression releases a suppression of 5HT function in those neurons leading to an increase in 5HT synthesis, increased SERT expression and 5HT2B receptor expression.
3) Presumably this causes a sort of double whammy for brain 5HT levels. Less SERT expression in the raphe leads to greater 5HT levels because reuptake mechanisms are decreased. In combination with this, locus ceruleus neurons take on a 5HT phenotype thereby increasing 5HT levels through the activation of a novel 5HT pathway in the CNS".
Answers
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Re: An Excellent Explaination of How SSRI's Inhibit Sert

Unread post by Answers »

The question is how do you increase WNT signalling and suppress mir-16?
Tree
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Re: An Excellent Explaination of How SSRI's Inhibit Sert

Unread post by Tree »

Answers wrote: Mon Dec 13, 2021 6:55 am The question is how do you increase WNT signalling and suppress mir-16?
Exactly, Simvastatin increases sert via wnt signalling independent of cholesterol lowering effects. It makes me very eager to try. We all need to research and find wnt activators.
ytho
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Re: An Excellent Explaination of How SSRI's Inhibit Sert

Unread post by ytho »

Tree wrote: Mon Dec 13, 2021 2:45 pm Exactly, Simvastatin increases sert via wnt signalling independent of cholesterol lowering effects. It makes me very eager to try. We all need to research and find wnt activators.
Hey Tree. I'm not an active poster here, but rather a silent user of the community, suffering for more than one year now. This topic seems very interesting to me.

Some comment you made in another thread made me come here. The comment was this one:
Tree wrote: Sat Nov 20, 2021 10:21 pm Serotonin isn't bad for erections it's essential when receptors are sensitive. The problem is we have excess serotonin in the synapse due to sert loss from ssri so receptors become desensitized. When serotonin doesn't bind and signal a response to the receptor then you get pssd symptoms. Think of pssd as being stuck in a withdrawal state where receptors don't normalize when stopping a drug. It's really that simple.

So based on that comment and this thread here it seems that you strongly believe that SERT loss / dysfunction is one major, if not THE major cause of this whole PSSD condition. It makes sense to me. Did you try Simvastatin so far? Or find any other potentially helpful wnt signal activators? I'm looking forward to hear from you, thanks.
Tree
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Re: An Excellent Explaination of How SSRI's Inhibit Sert

Unread post by Tree »

ytho wrote: Tue Dec 14, 2021 9:32 am
Tree wrote: Mon Dec 13, 2021 2:45 pm Exactly, Simvastatin increases sert via wnt signalling independent of cholesterol lowering effects. It makes me very eager to try. We all need to research and find wnt activators.
Hey Tree. I'm not an active poster here, but rather a silent user of the community, suffering for more than one year now. This topic seems very interesting to me.

Some comment you made in another thread made me come here. The comment was this one:
Tree wrote: Sat Nov 20, 2021 10:21 pm Serotonin isn't bad for erections it's essential when receptors are sensitive. The problem is we have excess serotonin in the synapse due to sert loss from ssri so receptors become desensitized. When serotonin doesn't bind and signal a response to the receptor then you get pssd symptoms. Think of pssd as being stuck in a withdrawal state where receptors don't normalize when stopping a drug. It's really that simple.

So based on that comment and this thread here it seems that you strongly believe that SERT loss / dysfunction is one major, if not THE major cause of this whole PSSD condition. It makes sense to me. Did you try Simvastatin so far? Or find any other potentially helpful wnt signal activators? I'm looking forward to hear from you, thanks.
Sorry for the delayed response to your post, my debilitating symptoms keep me off this forum. I think sert impairment is the most plausible theory from my extreme experiences and research collected from ssri's. Most, if not all, symptoms are associated with receptor desensitization. Sert loss causes these downstream effects. My experience supports this theory because I'm ultra sensitive to anything that raises serotonin. I also got mild serotonin syndrome twice from opioids and ginger, which permeantly worsened baseline. Both substances raise serotonin and agonize the 5ht1a receptors. Serotonin builds up in my system then crash. The only reasonable explanation is sert has been silenced from ssri's. It's a very noticeable pattern.

I have not tried simvaststatin yet but plan to sometime early next year. Some other wnt activators I found are icariin and zinc. The latter upregulates sert so it's probably because of Wnt activation.
I might try micro dosing zinc to see if there is subtle improvement over time.

This was the most informative article that supports sert loss theory. I hadn't found any information as to how ssri's inhibited sert. It gives me hope I'll be able to find relief some day.
ytho
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Re: An Excellent Explaination of How SSRI's Inhibit Sert

Unread post by ytho »

Thanks for your reply.

So far I’m not familiar with what or how severe your symptoms are, sorry for that. As for me, I mainly suffer from premature ejaculation, erectile dysfunction and loss of libido.

Back then when my pssd started but I didn’t know what it was called I tried to supplement with 5 HTP as I thought I need more serotonin after stopping the SSRI. I used that daily for up to two months and did not experience a thing. Nothing good, nothing bad. So I guess im either not that sensitive to serotonin or this SERT theory doesn’t apply to me?

Also during that time I added a daily dose of zinc to my vitamin supplements stack. Also didn’t do anything for me.

Maybe Simvastatin would be more potent, I don’t know.
Tree
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Re: An Excellent Explaination of How SSRI's Inhibit Sert

Unread post by Tree »

ytho wrote: Fri Dec 24, 2021 4:24 pm Thanks for your reply.

So far I’m not familiar with what or how severe your symptoms are, sorry for that. As for me, I mainly suffer from premature ejaculation, erectile dysfunction and loss of libido.

Back then when my pssd started but I didn’t know what it was called I tried to supplement with 5 HTP as I thought I need more serotonin after stopping the SSRI. I used that daily for up to two months and did not experience a thing. Nothing good, nothing bad. So I guess im either not that sensitive to serotonin or this SERT theory doesn’t apply to me?

Also during that time I added a daily dose of zinc to my vitamin supplements stack. Also didn’t do anything for me.

Maybe Simvastatin would be more potent, I don’t know.
I believe the severity of pssd is dependent on the degree to 5ht1a receptor sensitivity. Genetics, dosage, and length of ssri use will affect sert impairment in everyone differently which determines variation of symptoms. Before I crashed I had mild sexual symptoms but severe emotional bluntness/fatigue post crash both sexual and cognitive symptoms are extreme. It's pretty obvious what is happening from my experience because it's such a noticeable worsening in baseline symptoms. Do you have any cognitive symptoms from ssri?

I think zinc has a mild affect on wnt signalling so simovastin probably is more potent. Gsk3b inhibition also sees to activate wnt signalling. Gsk3b inhibition increases sert and increases 5ht1a
mrna expression by deaf1. Gsk3b and wnt seem to have a casual relationship.
MisterCharlie
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Re: An Excellent Explaination of How SSRI's Inhibit Sert

Unread post by MisterCharlie »

1. From a search: "Melatonin, icariin, and ghrelin, which activate Wnt/β-catenin signaling, have been shown to rescue Ti particle-impaired cellular function in MSCs and MC3T3-E1 cells in vitro"
https://www.researchgate.net/publicatio ... ng_pathway
(doesnt have the full text)

2. Inhibition of GSK3 by lithium, from single molecules to signaling networks
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282483/
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