Everything we knew about PSSD is wrong. Check out why.

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guacamo
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Everything we knew about PSSD is wrong. Check out why.

Unread post by guacamo »

Most prevalent hypothesis about PSSD is that SSRIs downregulate 5-HT1A autoreceptor which controls serotonin flow in the brain. In effect there is too much serotonin which is connected via negative feedback with dopamine and thus the result is PSSD.
Now let me tell you why this is wrong:
1. Neither 5-HT1A agonists or antagonists improve PSSD symptoms. Neither decreasing serotonin via depleting serotonin by taking l-tyrosine or l-dopa and 5-HT1A antagonism or increasing serotonin via taking precursor (Tryptophan or 5-HTP) improves PSSD Symptoms.

2. Increasing dopamine does not improve symptoms.

3. 5-HT2B receptors regulate serotonin release via the serotonin transporter, and are important both to normal physiological regulation of serotonin levels in blood plasma, and with the abnormal acute serotonin release produced by drugs such as MDMA.
Callebert J, Esteve JM, Hervé P, Peoc'h K, Tournois C, Drouet L, Launay JM, Maroteaux L (May 2006).
"Evidence for a control of plasma serotonin levels by 5-hydroxytryptamine(2B) receptors in mice" (PDF). The Journal of Pharmacology and Experimental Therapeutics. 317 (2): 724–31. doi:10.1124/jpet.105.098269. PMID 16461587. S2CID 16099098.
Doly S, Valjent E, Setola V, Callebert J, Hervé D, Launay JM, Maroteaux L (Mar 2008). "Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro". The Journal of Neuroscience. 28 (11): 2933–40. doi:10.1523/JNEUROSCI.5723-07.2008. PMC 6670669. PMID 18337424.

3a. 5-HT2B receptor is both necessary and sufficient for SSRI to work.
"We demonstrate for the first time that 5-HT2B receptors are expressed by serotonergic neurons of the raphe nuclei, which is consistent with a positive regulatory role for these receptors in synaptic 5-HT homeostasis.
""Based on the results presented herein, the activation of 5-HT2B receptors is necessary for acute and chronic SSRI actions, and chronic stimulation with a 5-HT2B receptor agonist is sufficient to mimic SSRI effects in wild type mice."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/

3a1. Agonising 5-HT2B receptor mimics ssri:
"Direct chronic activation of 5-HT2B receptors appears sufficient to induce chronic SSRI-like effects in the NSF test." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/

3a2. Blocking 5-HT2B receptor block SSRIs effect:
"Altogether, these results confirm that a lack of functional 5-HT2B receptors is sufficient to abolish the chronic actions of SSRIs at the cellular level."
"5-HT2B receptors are required for SSRI antidepressant acute and long-term effects, possibly by presynaptic modulation of extracellular 5-HT levels."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/

3a3. Every SSRI is 5-HT2B agonist:
"Fluoxetine and all other SSRIs are 5-HT2B Agonists - Importance for their Therapeutic Effects" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207076/

3a4. Different polymorphisms of gene SLC6A4 coding serotonin transporter have no effect on SSRI response:
With the results from one study the polymorphism was thought to be related to treatment response so that long-allele patients respond better to antidepressants Another antidepressant treatment response study did, however, rather point to the rs25531 SNP,[20] and a large study by the group of investigators found a "lack of association between response to an SSRI and variation at the SLC6A4 locus".
Kraft JB, Peters EJ, Slager SL, Jenkins GD, Reinalda MS, McGrath PJ, Hamilton SP (March 2007). "Analysis of association between the serotonin transporter and antidepressant response in a large clinical sample". Biological Psychiatry. 61 (6): 734–42. doi:10.1016/j.biopsych.2006.07.017. PMID 17123473.

4. SSRI block MDMA (which improves symptoms of PSSD) effects, MDMA works trough 5-HT2B receptor.
"acute pharmacological inhibition or genetic ablation of the 5-HT(2B) receptor in mice completely abolishes MDMA-induced hyperlocomotion and 5-HT release in nucleus accumbens and ventral tegmental area" https://pubmed.ncbi.nlm.nih.gov/18337424/

5. Every treatment with succes rate higher than 1 (inositol, st john wort, ssri reinstatement) involves 5-HT2B receptor.

a. SSRI - as i stated before.

b. St John Wort: Sjw releases serotonin and blocks serotonin reuptake without effect on serotonin transporter and cannot be explained purely by free intracellular sodium increase.

b1. St john wort act on releasing serotonin:
"St John’s wort extract and hyperforin induced a marked release of serotonin from synaptosomes preloaded with [3H]serotonin." https://pubmed.ncbi.nlm.nih.gov/12775192/

b2. St John Wort does not work via serotonin transporter:
"Gobbi et al.[47] reported that inhibition of serotonin reuptake by a methanolic St John’s wort extract and hyperforin is not due to a direct interaction with, and blockade of, the serotonin transporter because in both
compounds had no or only a very slight inhibitory effect on [3H]citalopram binding." https://pubmed.ncbi.nlm.nih.gov/12775192/

b3. It does not work purely but partially via increase in free intracellular sodium concentration:
"Calmidazolium (0.5 microM), an antagonist of the intracellular Ca2+-binding protein calmodulin significantly inhibited the hyperforin-induced shift of the IIV curve maximum and the slow-down of the activation kinetics. It did not, however, affect the delayed inhibition of P-current, indicating that the two stages of modulation are mediated by separate mechanisms." https://pubmed.ncbi.nlm.nih.gov/10954328/

c1. Inositol improves depression symptoms, but it does not work in people who did not respond to SSRIs and it does not amplify SSRI response:
"Studies that use inositol in persons who were resistant to SSRIs specifically have failed to find an antidepressant effect of 12g inositol over the course of four weeks and the combination of inositol with SSRIs failed to outperform SSRIs by themselves over the same time period.
https://pubmed.ncbi.nlm.nih.gov/10907738/
https://pubmed.ncbi.nlm.nih.gov/10023500/

It is clear that PSSD is related to 5-HT2B receptor, how however is unknown. From my scientific research i came to conclusion that SSRI somehow affect 5-HT2B so it does not release serotonin properly, because mind you increasing neurotransmitter amount in the synapse and neurotransmitter release are two different things and they both feel very different. So PSSD is not syndrome where you have too much serotonin, but rather its disease where serotonin is not released properly in the brain.
It would explain why modifying serotonin amount does not work, it's not the amount of serotonin that is wrong but the flow of serotonin.
Last edited by guacamo on Sat Jul 10, 2021 6:20 am, edited 5 times in total.
Janie
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Re: Everything we knew about PSSD is wrong. Check out why.

Unread post by Janie »

For me inositol had no effect other than worse brain fog. So I'm not sure it is true for my case.
DrugsAreBad
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Re: Everything we knew about PSSD is wrong. Check out why.

Unread post by DrugsAreBad »

This looks like really good research guacamo. Great work and thanks for sharing.
GIXXER
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Re: Everything we knew about PSSD is wrong. Check out why.

Unread post by GIXXER »

Interesting theory. I would agree that something within us has been blocked or turned off. Effexor which gave me PSSD, is odd because when I was on it the first time I still had a very high sex drive but extreme erectile dysfunction. Its the main reason why I stopped taking it. There was one day where everything returned back to normal, I woke up with an erection, and masturbated. I was back to normal, then over night it was like something was switched off inside me and I began my life with PSSD.
Tree
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Re: Everything we knew about PSSD is wrong. Check out why.

Unread post by Tree »

I don't know how people come up with these theories. You must be living under a rock or something. There have been many reports, myself included, of crashing from 5ht1a agonists. Agonists don't make things better but they sure as hell make things worse. This is why I'm convinced 5ht1a desensitization is the main cause of pssd.
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guacamo
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Re: Everything we knew about PSSD is wrong. Check out why.

Unread post by guacamo »

Tree wrote: Tue Jun 29, 2021 11:40 pm I don't know how people come up with these theories. You must be living under a rock or something. There have been many reports, myself included, of crashing from 5ht1a agonists. Agonists don't make things better but they sure as hell make things worse. This is why I'm convinced 5ht1a desensitization is the main cause of pssd.
It's because 5-HT1A is involved in sexuality. 5-HT2B is not, but 5-HT2B regulates serotonin release to every serotonin receptor which 5-HT1A is. So the theory is that fucked 5-HT2B regulates serotonin release and trough that 5-HT1A and other receptors are not working properly because of it. Also 5-HT1A agonists work on presynaptic receptors, only when taken with very high doses they are able to overcome presynaptic inhibition and work on postsynaptic 5-ht1a. 5-HT1A receptor might explain sexual side effects, but can't explain cognitive deficits, anhedonia, lack of emotions, lack of imagination, things that are prevalent in PSSD.

Also 5-HT2B is involved in dopamine signalling
"LY-266,097 is a research ligand which acts as a potent and selective antagonist for the 5-HT2B receptor, with more than 100x selectivity over the related 5-HT2A and 5-HT2C receptor subtypes. It has been used to study the role of the 5-HT2B receptor in modulating dopamine release in the brain, as well as its involvement in other processes such as allodynia."
https://en.wikipedia.org/wiki/LY-266,097

I can add also add as a trivia that St John wort upregulates presynaptic 5-HT1A not postsynaptic. It's different from what was previosly thought here, also when this paper is quoted in other works they mention postsynaptic 5-HT1A, which clearly points to the laziness or clear incompetence in reading from those who citate this paper in their research. I refer to this paper which is often mentioned on this forum https://pubmed.ncbi.nlm.nih.gov/9342771/. I have full access to this paper and there is stated clearly:
"we focused our attention on possible changes in the affinity and expression patterns of central serotonin receptors, which might account for the long term adaptations. In the present study, therefore, we investigated the action of a St. John's wort extract on the 5-HT1A autoreceptor and the postsynaptic 5-HT2 A receptor." 5-HT1A autoreceptor is located in presynaptic synapse.

https://pubmed.ncbi.nlm.nih.gov/12110997/ Hyperforin has affinity to 5-HT1A receptor, altrough there is not stated if it is agonist or antagonist of this receptor. As i said 5-HT1A is involved in PSSD, but it is not this receptor that is the problem by itself, but 5-HT2B which regulates serotonin release to this and other receptors.

screens from particular phytochemicals of St John Wort binding affinity
https://imgur.com/a/HOMGSjW hyperforin binding affinity
https://imgur.com/SlxmMbt hypericin binding affinity
https://imgur.com/kdLoz9w flavones binding affinity
https://imgur.com/QBfmYB4 whole st john wort binding affinity
Sadly they did not test every 5-HT receptor.
finities infinities
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Re: Everything we knew about PSSD is wrong. Check out why.

Unread post by finities infinities »

It's great that there are explicit pharmacodynamics tables for these substances like St. John's Wort. The only information missing is whether it is an antagonist or an agonist of a given receptor. This shows that in fact the drugs we were taking are not fully understood ( SSRIs and antipsychotic). Many drugs and herbs act as NMDA antagonists, for many antidepressants / antipsychotic drugs block NMDA receptors and sodium channel and in my opinion this is responsible for their main ,,tranquilizer discriminant effects". There should be more tables like the one about SJW.
For example, the discriminant stimulus of escitalopram is not replaced by hydroxytryptophan, which proves that escitalopram has some additional mechanisms of action that we do not know.
5ht1a theory is serious true! I confirmed it in me. Acute 5ht1a agonism reduces the symptoms of the disease and my ego + excess empathy death and causes intense sexual arousal then crash.
I believe the cannabinoid system is also the main culprit.
For example, a discriminatory stimulus of escitalopram can be simulated by combining: 5htp + cb1 agonists. Escitalopram appears to have cannabinoid effects and the escitalopram-induced PSSD has a cannabinoid component.
Remember that cb1 forms NMDA and 5ht2a heteromers!
And the 5ht2a antagonist (antipsychotic, mianserin) can cause severe PSSD via downstream- mGLUR2 and CB1 downregulation. Which leads to extreme serotonin elevation like in a psychedelic bad trip. (change in the perception of reality characteristic of psychedelics).
Yet another piece of information- antihistamines (diphenhydramine etc) induced PSSD. Antihistamine are also additional 5ht2a antagonist!
Pure H1 antagonist is anxiogenic and anti-libido, but antihistamines also acutely work anti-anxiety, and pro-sexual ... is effect from 5ht2a blockade!
Darman
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Re: Everything we knew about PSSD is wrong. Check out why.

Unread post by Darman »

Thanks for this. I have PSSD from escitalopram and have tried countless suplements that people have mentioned; with no sucsess. Do you have a reccomendation based on your idea of what is happening?
ErgogenicHealth
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Re: Everything we knew about PSSD is wrong. Check out why.

Unread post by ErgogenicHealth »

Hey guacamo,

Firstly, just wanted to say thank you for making this thread, there's some clear groundbreaking insights you are offering the community here.

Whenever I use any 5-HT1A agonist like ALCAR or yohimbine, usually it causes a temporary alleviation of PSSD, but this is quickly followed by a major crash.

Whenever I use St. John's Wort that is LOW in hyperforin, I can "cure" myself in a matter of 2 days, however, as soon as I stop SJW treatment, ALL symptoms revert.

Now one thing that surprises is me is why BERBERINE is not considered a "probe" here.

I also wanted to point out that Cyproheptadine, causes this incredible rebound glow effect (Alleviation of symptoms) for me that no one can really explain.

I am going to send you a DM.
Tree
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Re: Everything we knew about PSSD is wrong. Check out why.

Unread post by Tree »

guacamo wrote: Wed Jun 30, 2021 5:48 am
Tree wrote: Tue Jun 29, 2021 11:40 pm I don't know how people come up with these theories. You must be living under a rock or something. There have been many reports, myself included, of crashing from 5ht1a agonists. Agonists don't make things better but they sure as hell make things worse. This is why I'm convinced 5ht1a desensitization is the main cause of pssd.
It's because 5-HT1A is involved in sexuality. 5-HT2B is not, but 5-HT2B regulates serotonin release to every serotonin receptor which 5-HT1A is. So the theory is that fucked 5-HT2B regulates serotonin release and trough that 5-HT1A and other receptors are not working properly because of it. Also 5-HT1A agonists work on presynaptic receptors, only when taken with very high doses they are able to overcome presynaptic inhibition and work on postsynaptic 5-ht1a. 5-HT1A receptor might explain sexual side effects, but can't explain cognitive deficits, anhedonia, lack of emotions, lack of imagination, things that are prevalent in PSSD.

Also 5-HT2B is involved in dopamine signalling
"LY-266,097 is a research ligand which acts as a potent and selective antagonist for the 5-HT2B receptor, with more than 100x selectivity over the related 5-HT2A and 5-HT2C receptor subtypes. It has been used to study the role of the 5-HT2B receptor in modulating dopamine release in the brain, as well as its involvement in other processes such as allodynia."
https://en.wikipedia.org/wiki/LY-266,097

I can add also add as a trivia that St John wort upregulates presynaptic 5-HT1A not postsynaptic. It's different from what was previosly thought here, also when this paper is quoted in other works they mention postsynaptic 5-HT1A, which clearly points to the laziness or clear incompetence in reading from those who citate this paper in their research. I refer to this paper which is often mentioned on this forum https://pubmed.ncbi.nlm.nih.gov/9342771/. I have full access to this paper and there is stated clearly:
"we focused our attention on possible changes in the affinity and expression patterns of central serotonin receptors, which might account for the long term adaptations. In the present study, therefore, we investigated the action of a St. John's wort extract on the 5-HT1A autoreceptor and the postsynaptic 5-HT2 A receptor." 5-HT1A autoreceptor is located in presynaptic synapse.

https://pubmed.ncbi.nlm.nih.gov/12110997/ Hyperforin has affinity to 5-HT1A receptor, altrough there is not stated if it is agonist or antagonist of this receptor. As i said 5-HT1A is involved in PSSD, but it is not this receptor that is the problem by itself, but 5-HT2B which regulates serotonin release to this and other receptors.

screens from particular phytochemicals of St John Wort binding affinity
https://imgur.com/a/HOMGSjW hyperforin binding affinity
https://imgur.com/SlxmMbt hypericin binding affinity
https://imgur.com/kdLoz9w flavones binding affinity
https://imgur.com/QBfmYB4 whole st john wort binding affinity
Sadly they did not test every 5-HT receptor.
When I crashed from 5ht1a agonist, it was one day from the next extreme worsening of both cognitive (brain fog, emotional bluntness, anhedonia, etc) and sexual symptoms. Baseline has pretty much stayed constant since. 5ht1a receptors must then have an affect on cognitive symptoms too. Presynaptic 5ht1a receptors also inhibit serotonin release. 5ht2b receptors down regulate in response to agonism, which would inhibit serotonin release and ssri effects. Not saying 5ht2b receptors don't play a role in pssd, I just think 5ht1a desensitization is the main cause. The desensitization of 5ht receptors is most likely caused by permanent sert loss.

Inositol also makes symptoms worse and gives me terrible migraines. I never had migraines before pssd. It increases 5ht release in the raphe so that's probably the reason. We already have too much 5ht release in the raphe from 5ht1a desensitization induced by ssri.
Last edited by Tree on Fri Jul 02, 2021 12:48 am, edited 1 time in total.
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