I am going to drop a major bomb soon

[Impermanence]

SSRI also can cause genital shrinkage so from the theory that PSSD is a some of SSRI's side effects which still persist after the treatment, then yes, it is very much possible.

Hi mate. I disagree with you. PSSD is different from side effect of SSRI. I used to use SSRI to my patients ( now I'm much more precautionous) and numbness, genital anesthesia never happen. SSRI are also a good treatment of anhedonia.
For me, as I already said there is something common in sexual persistent Dysfonction. Is it NO production? Pre frontal hypo metabolism (trigger by 5Hta1 desensitization or mess in neurosteroid or else)? Not sure.
That's why many of us get PSSD after SSRI not during...
That's what I think, just my opinion. No one know for the moment

[cdraham]

SSRI also can cause genital shrinkage so from the theory that PSSD is a some of SSRI's side effects which still persist after the treatment, then yes, it is very much possible.

Hi mate. I disagree with you. PSSD is different from side effect of SSRI. I used to use SSRI to my patients ( now I'm much more precautionous) and numbness, genital anesthesia never happen. SSRI are also a good treatment of anhedonia.
For me, as I already said there is something common in sexual persistent Dysfonction. Is it NO production? Pre frontal hypo metabolism (trigger by 5Hta1 desensitization or mess in neurosteroid or else)? Not sure.
That's why many of us get PSSD after SSRI not during...
That's what I think, just my opinion. No one know for the moment

If you look at what happens biochemically beyond serotonin, cortisol also rises alot in withdrawal and at the first pill. I had the studies somewhere in my notes but I can't find them now because my memory is gone. Also ssris interfere with retinoid metabolism. If you check some members here, you will see many tested for evidence of infections after ssri (including me), imo ssris trigger something similiar to CFS by inducing cortisol, in those that have genetic predisposition and some underlying pathogens that can reactivate and go chronic.

If you have chronic infections of mycoplasma or lyme etc, these raise ammonia in the brain which is a potent neurotoxin, it can cause brain hypofunction because it boosts GABA, it also increases allopregnanolone. Ammonia causes NMDA hypofunction. Many drugs use glutamate to excert their effects so no wonder some of us lost all response to psychedelics, etc, imo ammonia blocks Nmda and this is the reason for the negative symptoms of schizophrenia etc.

Beyond this you will get the immune response to chronic infections like in lyme, which can be temporarily reversed by high dose corticosteroids (see Windows on prednisone and mifepristone)

To cure this type, you can try boosting the immune response and methylation cycle, but if you have some pathogens like lyme or mycoplasma probably something is needed to kill those infections. It's the reason why some ppl worsen when boosting gluathione. Or the "methyl donor crashes" some talk about here is imo the methylation cycle starting up again by correcting one of the deficient pathways, so you get the negative detox reaction.

If you have severe pssd you can try reishi with oat bran, i can guarantee you will respond to it in a negative way, because it boosts the immune response

[Tree]

Some of these are definetly PSSD related, why some do have more severe symptoms, it's from this 5-HT1A theory that these people pre-synaptic 5-HT1A receptor is desensitized more severely. PFS and PSSD do have some common symptoms, but correlation does not mean causation.

Exactly, I've been saying this on the forum for years. I know it's the case from experience because how severely all of my cognitive (brain fog, anhedonia, fatigue, emotional bluntness, memory decline, insomnia etc) and sexual symptoms (erectile dysfunction, libido loss, genital shrinkage) declined after crashing from a 5ht1a agonist. Before crashing I had mild pssd, after crashing, my pssd became severe and debilitating. 5ht1a desensitization causes sexual and cognitive symptoms. For some reason, once the receptors downregulate substantially, the receptors become stuck in the new desensitized state. Maybe the 5ht1a receptor is being silenced by over expression of regulators of g protein signaling RGS. Ghost did some research on this years ago.

[cdraham]

Some of these are definetly PSSD related, why some do have more severe symptoms, it's from this 5-HT1A theory that these people pre-synaptic 5-HT1A receptor is desensitized more severely. PFS and PSSD do have some common symptoms, but correlation does not mean causation.

Exactly, I've been saying this on the forum for years. I know it's the case from experience because how severely all of my cognitive (brain fog, anhedonia, fatigue, emotional bluntness, memory decline, insomnia etc) and sexual symptoms (erectile dysfunction, libido loss, genital shrinkage) declined after crashing from a 5ht1a agonist. Before crashing I had mild pssd, after crashing, my pssd became severe and debilitating. 5ht1a desensitization causes sexual and cognitive symptoms. For some reason, once the receptors downregulate substantially, the receptors become stuck in the new desensitized state.

If you take this theory, why did some here get full reversal of symptoms on high dose corticosteroids or mifepristone. Makes me think there are several types of pssd. Which seems unlikely but who knows

[Tree]

Some of these are definetly PSSD related, why some do have more severe symptoms, it's from this 5-HT1A theory that these people pre-synaptic 5-HT1A receptor is desensitized more severely. PFS and PSSD do have some common symptoms, but correlation does not mean causation.

Exactly, I've been saying this on the forum for years. I know it's the case from experience because how severely all of my cognitive (brain fog, anhedonia, fatigue, emotional bluntness, memory decline, insomnia etc) and sexual symptoms (erectile dysfunction, libido loss, genital shrinkage) declined after crashing from a 5ht1a agonist. Before crashing I had mild pssd, after crashing, my pssd became severe and debilitating. 5ht1a desensitization causes sexual and cognitive symptoms. For some reason, once the receptors downregulate substantially, the receptors become stuck in the new desensitized state.

If you take this theory, why did some here get full reversal of symptoms on high dose corticosteroids or mifepristone. Makes me think there are several types of pssd. Which seems unlikely but who knows

It was temporary. People also claim to crash from them. It's probably because corticosteroids cause 5ht1a desensitization.

[MindChanger]

I edited the main post, u can check this up.

Thanks, I read your theory. I have a question..

How does this explain the chronic fatigue, loss of muscle, head pressure and other symptoms seen in severe pssd?

You forget that serotonin is a potent Immune Cell Modulator (https://www.frontiersin.org/articles/10 ... 00186/full). A downregulation of the presynaptic autoreceptor would lead to an increased binding of serotonin to all 5HT receptors. The consequences in predisposed individuals (those with defective immune genes) could be unexpected. 5HT results in Th1/Th17 shift, so this theory could easily explain all of the symptoms you mentioned, including CD57+ dysfunction, although molecular mechanisms are still unknown.

Moreover, elevated serotonin would directly alter other neurotransmitters through G-coupled proteins and heterodimers as well as sodium/potassium/calcium homeostasis. Let me provide you a few examples. 5HT2A has a connection with mGlur, Cb1, D2. 5HT2C directly inhibits dopamine and norepinephrine. 5HT3 is a ligand-gated ion channel similarly to GABA or NMDA, which pushes sodium into a cell. It is also worth mentioning that 5HT3 is one of those recetors that do not work in negative feedback manner (it is upregulated from both agonism and antagonism), and they are tend to recover for a longer period of time (Benzo-withdrawal etc.).

I'd also like to say that my Th2 cytokines are undetectable on my blood tests, while my Th1 cytokines are still in the perfect middle of the range. Moreover, my tryptophan and serotonin are also elevated. And yes, I had a great window with dexamethasone. I still believe that while serotonin is a cause of some symptoms, other symptoms like anhedonia, inflammation, cognitive dysfunction, fatigue are mostly caused by immune dysfunction induced by serotonin in predisposed individuals.

Murine basophils were found to participate in the Th2 polarization by instantly secreting lots of IL-4, whereas 5-HT could downregulate this IL-4 production by basophils in vitro and in vivo

.

I would like to say thanks to guacamo for his work. For me it is still not clear how SSRIs do result in permanent changes in 5HT1A autoreceptor, but I must admit that collected data on cured cases, and provided studies were indeed extremely intriguing. I am also curious what you are trialing regarding your theory as I have researched all compounds that interfere with serotonin.

[guacamo]

I agree with you that PSSD may be due to downstream effect of 5-HT1A and i am aware on it's interactions with other receptors. The question is what would be more efficient way and more hopefull one, to attack the main cause that started the whole pathological signal transduction (it's arche) or actually finding in what part of said signal transduction did 5-HT1A have influence on certain PSSD symptoms, for i think we both agree is beyond our possibilities.

[bigpoppa10040]

Some of these are definetly PSSD related, why some do have more severe symptoms, it's from this 5-HT1A theory that these people pre-synaptic 5-HT1A receptor is desensitized more severely. PFS and PSSD do have some common symptoms, but correlation does not mean causation.

Exactly, I've been saying this on the forum for years. I know it's the case from experience because how severely all of my cognitive (brain fog, anhedonia, fatigue, emotional bluntness, memory decline, insomnia etc) and sexual symptoms (erectile dysfunction, libido loss, genital shrinkage) declined after crashing from a 5ht1a agonist. Before crashing I had mild pssd, after crashing, my pssd became severe and debilitating. 5ht1a desensitization causes sexual and cognitive symptoms. For some reason, once the receptors downregulate substantially, the receptors become stuck in the new desensitized state.

If you take this theory, why did some here get full reversal of symptoms on high dose corticosteroids or mifepristone. Makes me think there are several types of pssd. Which seems unlikely but who knows

I’m going to assume there is an immune system component, more specifically an autoimmune reaction, which is what I’ve thought it was for years. It makes 0 sense that people can take high dose anabolic steroids or TRT and get worse or have no effects. That’s not explained by any receptor other than androgen receptor. Autoimmune reaction may occur after the withdrawal of the substance too

[heymartinn]

Thanks for your research and input. What are your thoughts on using fenclonine for 4-6 weeks as way of gaining some lasting positive effects and hopefully upregulating pre-synaptic 5ht1a r?

[cdraham]

I edited the main post, u can check this up.

Thanks, I read your theory. I have a question..

How does this explain the chronic fatigue, loss of muscle, head pressure and other symptoms seen in severe pssd?

You forget that serotonin is a potent Immune Cell Modulator (https://www.frontiersin.org/articles/10 ... 00186/full). A downregulation of the presynaptic autoreceptor would lead to an increased binding of serotonin to all 5HT receptors. The consequences in predisposed individuals (those with defective immune genes) could be unexpected. 5HT results in Th1/Th17 shift, so this theory could easily explain all of the symptoms you mentioned, including CD57+ dysfunction, although molecular mechanisms are still unknown.

Moreover, elevated serotonin would directly alter other neurotransmitters through G-coupled proteins and heterodimers as well as sodium/potassium/calcium homeostasis. Let me provide you a few examples. 5HT2A has a connection with mGlur, Cb1, D2. 5HT2C directly inhibits dopamine and norepinephrine. 5HT3 is a ligand-gated ion channel similarly to GABA or NMDA, which pushes sodium into a cell. It is also worth mentioning that 5HT3 is one of those recetors that do not work in negative feedback manner (it is upregulated from both agonism and antagonism), and they are tend to recover for a longer period of time (Benzo-withdrawal etc.).

I'd also like to say that my Th2 cytokines are undetectable on my blood tests, while my Th1 cytokines are still in the perfect middle of the range. Moreover, my tryptophan and serotonin are also elevated. And yes, I had a great window with dexamethasone. I still believe that while serotonin is a cause of some symptoms, other symptoms like anhedonia, inflammation, cognitive dysfunction, fatigue are mostly caused by immune dysfunction induced by serotonin in predisposed individuals.

Murine basophils were found to participate in the Th2 polarization by instantly secreting lots of IL-4, whereas 5-HT could downregulate this IL-4 production by basophils in vitro and in vivo

.

I would like to say thanks to guacamo for his work. For me it is still not clear how SSRIs do result in permanent changes in 5HT1A autoreceptor, but I must admit that collected data on cured cases, and provided studies were indeed extremely intriguing. I am also curious what you are trialing regarding your theory as I have researched all compounds that interfere with serotonin.

Thanks, I read about serotonin effect on immune cells. However I think this is more relevant to how pssd begins. It changes some parameters of immune response so chronic infections can manifest.

Im positive in IgA and IgG for mycoplasma pneumoniae. I have low cd57.

I don't know what 5ht1a has to do with this.

The permanent low Cd57 cells are not caused by serotonin. It's caused by infections, im even positive for them beeing active.