My theory - Etiology of PSSD and potential treatment.

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guacamo
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Re: My theory - Etiology of PSSD and potential treatment.

Unread post by guacamo »

Yes i should word it better that it is my assumption that the fatigue came from magnesium, poor wording on my side, sorry. Also i need to mention that i took isolated inositol before and it did not help. Today i had no fatigue from magnesium which is very weird because magnesium always induces insane fatigue to me, which speaks that there is some interaction going on, if for good, time will tell.
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Meso
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Re: My theory - Etiology of PSSD and potential treatment.

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I think you are onto something here.

Last year, I researched 5HT2B receptors in relation to SERT and SSRIs. 5HT2B receptors directly control SERT's activity and phosphorylation. It is unknown how this plays into PSSD and the symptoms of high serotonin, but if SERT is hyperphosphorylated after SSRI withdrawal, it might mean it's essentially silenced.

"In the presence of 5-HT, the 5-HT(2B) receptor-PKC coupling promotes additional phosphorylations of both SERT and Na(+),K(+)-ATPase alpha-subunit, impairing the electrochemical gradient necessary to 5-HT uptake. SERT hyperphosphorylation also affects antidepressant recognition. Finally, such 5-HT(2B) receptor-mediated control of SERT activity operates in primary neurons from raphe nuclei."
https://pubmed.ncbi.nlm.nih.gov/16940156/

SSRIs directly downregulate SERT and I believe that SERT downregulation/silencing plays a significant role in PSSD symptoms. As for L-type calcium channels, I've read recently that SSRIs blunt up the GABA-B mediated suppression of L-type channels in the DRN, leading to increase in tonic serotonin firing via activation of L-type calcium channels there so I don't think increasing those channels activation is the answer.

Goodluck with your trial!
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guacamo
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Re: My theory - Etiology of PSSD and potential treatment.

Unread post by guacamo »

For Protein kinase C to be activated it needs phosphatidylinositol 4,5-bisphosphate to convert to inositol triphosphate and diacylglycerol and increased Ca2+, signal transduction that is mediated by 5-HT2B. It then regulates genes and cell proliferation.
Tree
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Re: My theory - Etiology of PSSD and potential treatment.

Unread post by Tree »

There's probably a different, more direct way ssri's has silenced sert but the 5ht2b receptor seems to have at least an indirect affect on sert from these studies. Does this mean it would be beneficial to block 2b receptors? Inositol would not be good for pssd if it activates pkc.

"5-HT itself reduced the PKC-mediated phosphorylation and internalization of the SERT and SSRIs blocked the effect of 5-HT (Ramamoorthy and Blakely, 1999).
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guacamo
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Re: My theory - Etiology of PSSD and potential treatment.

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No, because the problem does not lie in the 5-HT2B itself. It is actually very direct way 5-HT2B affect SERT.
ErgogenicHealth
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Re: My theory - Etiology of PSSD and potential treatment.

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Researchers have demonstrated that parthenolide noncompetitively inhibited serotonin (5-HT)-mediated spasmogenic response of indirect-acting 5-HT agonists in isolated rat stomach fundus preparation. Parthenolide noncompetitively antagonized the contractions elicited by the serotonergic drugs fenfluramine and dextroamphetamine on the fundal tissue. The mechanism of action associated with parthenolide does not involve the inhibition of 5-HT2 receptors directly, but rather occurs at the level of 5-HT stored in vesicles of the intramural neurons of fundal tissue.[35]

Any interest in Feverfew?

Parthenolide (5 x 10(-5) mol/L) followed the same trend. However, Feverfew extract (1 x 10(-5) mol/L) potently and directly blocked 5-HT2B and 5-HT2A receptors and neuronally released 5-HT. At 5 x 10(-5) mol/L the extract potently and irreversibly blocked the above. Both parthenolide and Feverfew extract showed a time-dependency in their action. The extract when degraded thermally upto 10% could significantly block the 5-HT receptors and neuronal release of 5-HT, however, on further degradation it lost its inhibitory capacity markedly. Similar results were observed in rats fed orally with undergraded and degraded Feverfew powder and injected i.p. with parthenolide. Feverfew powder was more effective than any of its extracts or pure parthenolide.

Conclusion: Feverfew powder is more potent than any of its extract or parthenolide alone in its antiserotonergic activity. Degraded Feverfew extracts show a marked decrease in their antiserotonergic activity. With thermally degraded Feverfew powder containing less contents of parthenolide no built-up antiserotonergic responses were observed after one month. This ascertains that Feverfew should be dispensed in a properly stabilized form wherein its parthenolide content is not degraded to less than 90% of the original content
Tree
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Re: My theory - Etiology of PSSD and potential treatment.

Unread post by Tree »

guacamo wrote: Fri Jul 16, 2021 6:33 am No, because the problem does not lie in the 5-HT2B itself. It is actually very direct way 5-HT2B affect SERT.

Where does the problem lie? Pkc activation mediated by 2b receptors must not be helping anything.
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guacamo
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Re: My theory - Etiology of PSSD and potential treatment.

Unread post by guacamo »

In inositol metabolism and Ca2+ signaling.
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Meso
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Re: My theory - Etiology of PSSD and potential treatment.

Unread post by Meso »

guacamo wrote: Sat Jul 17, 2021 7:46 am In inositol metabolism and Ca2+ signaling.
I don't think it's that simple. You are onto something here for sure, but it's not the only root issue. There are several factors we must consider. Sex hormone receptors are methylated/silenced. I keep seeing people with normal testosterone levels yet they lack nocturnal erections and morning wood. Also, the genital numbness might be peripheral; a problem affecting the spinal cord, I reckon.

Either way, the only way we can know whether your hypothesis is solid is through good ol` trial and error. I appreciate the fact that you are trying this on yourself. Thank you for that. I always try things on myself to share with other members my reactions before they try it themselves.

That said, several of my patients have found relief with supraphysiological TRT + lithium + progesterone, through trial-and-error, which points towards methylation and sex hormone receptors' malfunction.
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lastround360
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Re: My theory - Etiology of PSSD and potential treatment.

Unread post by lastround360 »

guacamo wrote: Wed Jul 14, 2021 1:51 pm If you do not want to wait for my trial, then it should go like this: 300mg of elemental magnesium l-threonate at bed time, 150mg of elemental magnesium l-threonate upon waking up
What made you chose this dosage? I see most magnesium l-threonate comes in 2000mg dosages. Is it possible to take too much?
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