My theory - Etiology of PSSD and potential treatment.

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guacamo
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My theory - Etiology of PSSD and potential treatment.

Unread post by guacamo »

Read the full post tl;dr too
Hi, i already created 2 topics about PSSD etiology but i will repeat some of the informations, because this will be complementary topic.
PSSD is iatrogenic dysfunction where brain homeostasis is dysfunctional due to the previous taking of the SSRI. It manifests in sexual symptoms but not only, it also includes things like anhedonia, lack of imagination, lack of emotions, low energy. Symptoms appear first during taking SSRIs and do persist after discontinuation. Now let's have a look at what SSRIs really do to our brains:

The most known effect SSRIs induce in our brain is downregulation of presynaptic 5-HT1A receptor in raphe nuclei, which was previously thought to mediate the effects of the SSRI. The idea is that dysregulated (too much)serotonin flow inhibits dopamine flow in the brain and dopamine is known to enhance sexual function, thus reduced dopamine=reduced sexual function. But this idea does have major flaws. Now i will tell you why PSSD is not too much serotonin:

1. Neither 5-HT1A agonists or antagonists help rebalance homeostasis, they may induce crash or help temporarily but they do not reverse the changes and they do not help relief PSSD in a major way.

2. Dopamine precursors, agonists and reuptake inhibitors do not help relieve PSSD symptoms in a way that would indicate that the problem lies in dopamine transmission.

3. It is known that the effect of the SSRI is also mediated by 5-HT2B receptor, while it's function is poorly understood it is known that this receptor is involved in more pleiotropic way in neural transmission than 5-HT1A - which would explain sexual side effects but not the others.

4. 5-HT2B is necessary for SSRIs 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/

5. Chronic 5-HT2B agonism mimics SSRIs effect in novelty-suppressed feeding in mices:
"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/

6. 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/

7. 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/

8. SSRIs changes the way 5-HT2B receptor on astrocytes works, in effect this receptor no longer does the work it's supposed to do:
"In contrast editing of the receptor was obvious after 3 days of treatment, and after 7 days the edited receptor no longer responded to serotonin by an increase in activity measured as the ability of serotonin to evoke release of 3H-inositol phosphate (IP) from labeled IP3 or phosphorylation of ERK1/2." https://www.hindawi.com/journals/jst/2014/593934/

9. Another role of 5-HT2B receptor:
5-HT2B "Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and down-stream signaling cascades and promotes the release of Ca2+ ions from intracellular stores (PubMed:8143856, PubMed:8078486, PubMed:8882600, PubMed:18703043, PubMed:23519215, PubMed:28129538)."

10. After inositol connects with it's receptor IP3, it raises intracellular calcium, which produces calcium eflux from endoplasmic reticulum, since SSRIs induce changes in 5-HT2B receptor it no longer is able to evoke release of inositol phosphate, it does not raise intracellular Ca2+ and whole process is disrubted.

11. SSRI's at first induce Ca+2 release which explain why some people benefit from reinstating SSRIs at first, but after continous intake SSRIs abolish Ca2+ increase and that is the moment where sexual side effects kick in.
"In contrast to the ability of fluoxetine (and many transmitters) to acutely cause an increase Ca+2 , chronic treatment with fluoxetine rapidly abolishes or reduces transmitter and fluoxetine-induced Ca+2 increase." https://www.hindawi.com/journals/jst/2014/593934/

12. Current data states that astrocytes play dominant role in depression and SSRIs change how astrocytes work:
"They may play a key role in the antidepressant mechanism of SSRIs. Given the dominant role ascribed to neurons in the mechanisms of SSRIs and other psychiatric drugs it may appear surprising that studies found the major chronic impact of SSRIs in the fluoxetine-treated mice to be on astrocytes. However they are consistent with the growing evidence for a major role of these cells in major depression and its therapy studied in patients (Abdallah et al., 2014a,b), postmortem brain (Rajkowska and Stockmeier, 2013) or in models of this disease (Gosselin et al., 2009; Banasr et al., 2010)." https://www.frontiersin.org/articles/10 ... 00025/full

13. Two most succesfull supplements (inositol and SJW) in one way or another work via IP3. St john wort has direct affinity for IP3 receptor, and myo-inositol via metabolism changes in the body is converted to phosphatidylinositol.
It [St john wort] also acts as a receptor antagonist at adenosine, benzodiazepine, GABA-A, GABA-B, and inositol triphosphate receptors, which regulate action potentials caused by neurotransmitters (Chavez and Chavez 1997; Jellin et al. 2002).

PSSD is due to low intracellular Ca2+, because of 5-HT2B editing, SOC channels downregulation, VGCCs meddling, deactivating IP3 and RyR3 mediated Ca2+ release.

The rest is debatable.

15. People are not cured by inositol because they have low intracellular magnesium, which is necessary for phosphatidylinositol 3-kinase to work(it is also possible that inositol lowers magnesium levels):
"TRPM7 (Nadler et al., 2001) and TRPM6 (Schlingmann et al., 2002) were the first channels identified as being able to transport Mg2+ into mammalian cells. While Fleig and her group (Nadler et al., 2001) reported a preferential Mg2+ permeation through the LTRPC7 channel (i.e. TRPM7 based on the current nomenclature), genetic analysis (Schlingmann et al., 2002) indicated, more or less at the same time, that TRPM6, another member of the melastatin subfamily of TRP channels, exhibits a selective Mg2+ permeation."

"Interestingly, TRPM7 activation only takes place in the presence of a physiological cellular [Mg2+]i, whereas reducing this concentration below
its physiological level with EDTA- AM results in a PLC-mediated inactivation of TRPM7 activity, most likely via PIP2 depletion (Langeslag et al., 2007)."\

"The interaction between TRPM7 and phosphatidyl-inositol metabolites is further supported by the observation that TRPM7 is required for a sustained phosphoinositide-3-kinase signalling in lymphocytes
(Sahni and Scharenberg, 2008). In the presence of a physiological concentration of extracellular Mg2+, TRPM7-deficient cells rapidly down-regulate their rate of growth as a result of a
signalling deactivation downstream PI3-Kinase (Sahni and Scharenberg, 2008), the phenotype being rescued by supplementing the culture medium with Mg2+ (Sahni and Scharenberg, 2008)."

more info on the role of magnesium:

"Inhibition of IP3- induced Ca2+ release from the endoplasmic reticulum, chelation of cytosolic Ca2+, or inhibition of Ca2+ entry at the plasma membrane level all result in the complete inhibition of Mg2+ extrusion from the hepatocytes"

"in the absence of PKC activation or following RACK1 over-expression, RACK1 can bind to TRPM6, and possibly TRPM7, at the level of the kinase domain and inhibit the channel activity"

"Protein kinase C activation is only part of the integral response of hormones like angiotensin-II or vasopressin. The interaction of these hormones with their receptor, in fact, activates phospholipase C which,
in turn hydrolyses PIP2 to generate diacylglycerol (DAG) and IP3. In turn, these two molecules activate protein kinase C and IP3 receptor in the ER, respectively. Activation of the latter receptor results in a marked
but transient increase in cytosolic Ca2+, and in a more sustained entry of Ca2+ through the capacitative Ca2+ entry mechanism. Hence, Ca2+ signalling is an integral component of the cellular response elicited by these hormones.
Yet, the contribution of this second messenger in mediating Mg2+ accumulation is poorly defined. Liver cells loaded with Bapta-AM, which effectively chelates cytosolic Ca2+, are unable to extrude and accumulate Mg2+
following stimulation by phenylephrine and PMA, respectively (Romani et al., 1993b). The artificial increase in cytosolic Ca2+ elicited by thapsigargin administration also prevents Mg2+ accumulation (Romani et al., 1993b)
and actually induces a Mg2+ extrusion from the liver cell if applied for more than 3-5 min (Romani et al., 1993b; Fagan and Romani, 2001). Because of the different time-scale and amplitude of the changes in cellular Ca2+ and Mg2+ content
(Romani et al., 1993b), it is difficult to properly correlate these experimental variations. Cytosolic free Ca2+ transiently increases several orders of magnitude while cytosolic free Mg2+, which is already in the millimolar or submillimolar range,
increases by ~10-15% (Fatholahi et al., 2000) at the most, although in absolute terms this amount is far larger than the overall change in cytosolic Ca2+ mass."


"The experimental evidence that mammalian cells accumulate or extrude Mg2+ under a variety of experimental conditions suggests the presence of a sensor for the cytosolic Mg2+ concentration,
whereby the cell would operate accordingly either extruding the excess cation or accumulating it to restore the ‘set-point’. Compelling evidence for the presence of such a sensor mechanism is provided
by the observation that prolonged exposure to 0mM [Mg2+]o decreases cytosolic free Mg2+ concentration by approximately 50% in cardiac ventricular myocytes (Quamme and Rabkin, 1990),
MDKC (Quamme and Dai, 1990), or MDCT cells (Dai et al., 1997). The new cytosolic Mg2+ level is maintained as long as the cells are incubated in the presence of 0 mM [Mg2+]o,
but returns to the normal level as soon as [Mg2+]o is increased (Quamme and Rabkin, 1990; Quamme and Dai, 1990; Dai et al., 1997), in a frame of time that is directly proportional to the extracellular
Mg2+ concentration utilized (Quamme and Rabkin, 1990; Quamme and Dai, 1990; Dai et al., 1997). The process is prevented by the presence of the L-type Ca2+-channel inhibitors verapamil or nifedipine,
or La3+ in the extracellular milieu (Quamme and Rabkin, 1990). The absence of significant changes in cytosolic free Ca2+ concentration under these experimental conditions suggests a direct effect of these inhibitory agents
on the Mg2+ entry mechanism (Quamme and Rabkin, 1990). This observation led the authors to propose the operation of a specific Mg2+ channel in these cells, anticipating the identification of TRPM6 (Schlingmann et al., 2002)
and TRPM7 (Nadler et al., 2001) as specific Mg2+ channels."

source: https://www.ncbi.nlm.nih.gov/books/NBK507258/


tl;dr - read the full post if you care about your health, but if i have to summarise is that SSRIs induce changes in 5-HT2B receptor, they no longer work they way they should, they also initially induce calcium release (this is the moment where SSRIs reinstatement for a brief moment reliefs the symptoms), to abolish it almost completely later on (this is where PSSD kicks in). In some people this change persist after stopping medication. What differed those who benefited from inositol from those who did not is that they had functional TRPM7, for 5-HT2B to operate functioning TRPM7 is necessary and for TRPM7 to function intracellular magnesium is necessary, those who benefited from inositol had functioning TRPM7 receptor, it is possible that polymorphism of this receptor in PSSD sufferers is different from the rest of the population, and for it to function they need higher magnesium intake than the rest. Those who have PSSD may react with crash to the magnesium so their magnesium intake in the diet is poor and if they supplement with standard magnesium it takes several months for intracellular magnesium stores to normalize, the best solution is to take magnesium l-threonate orally or transdermal magnesium which raises magnesium level the fastest, prepare however because it is very likely that this will induce hardcore crash that will last a week or two, if you do not want to crash wait out 3-5 weeks, because i already take inositol with magnesium l-threonate and i will be able to tell you if this works or not. I am 100% sure about the cause, but only 60% sure about the cure, there is very small likehood that actually what needs to be done is to replace magnesium with ssri, but magnesium theory has much more data to back it up so first let's try this. 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 (it has to induce at least mild brain fog and crash) and 20g of inositol at 8pm, before bed time. (in every cured case it was taken before bed)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896866/
https://www.tandfonline.com/doi/abs/10. ... 21.1929732
https://www.uniprot.org/uniprot/P41595
https://en.wikipedia.org/wiki/Calcium_channel
https://en.wikipedia.org/wiki/5-HT2B_receptor
https://link.springer.com/article/10.1007/BF01787021
https://academic.oup.com/icb/article/41/4/1009/2046729
https://journals.plos.org/plosone/artic ... ne.0206986
https://pubmed.ncbi.nlm.nih.gov/16688720/
https://www.jbc.org/article/S0021-9258(19)74306-3/pdf
https://onlinelibrary.wiley.com/doi/ful ... /cns.13634
https://onlinelibrary.wiley.com/doi/ful ... 10.06795.x
https://link.springer.com/article/10.10 ... 20-00569-0
https://www.ncbi.nlm.nih.gov/books/NBK92750/
https://www.nature.com/articles/tpj201124
https://www.tandfonline.com/doi/abs/10. ... 21.1929732
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556207/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539076/
https://web.williams.edu/imput/synapse/pages/IIA1.htm
https://pubmed.ncbi.nlm.nih.gov/24854234/
https://www.hindawi.com/journals/jst/2014/593934/
https://www.ahajournals.org/doi/full/10 ... 0.25714.D9
https://hal.archives-ouvertes.fr/hal-01 ... rt0206.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670669/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381222/
https://pubmed.ncbi.nlm.nih.gov/9760040/
https://pubmed.ncbi.nlm.nih.gov/15629140/
https://journals.physiology.org/doi/ful ... 00006.2016
https://www.sciencedirect.com/science/a ... 3418306225

Information included in this post cannot be taken as medical advice and does not replace it.
Last edited by guacamo on Sun Jul 18, 2021 11:03 am, edited 19 times in total.
Sb919
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Re: Etiology of PSSD and potential treatment.

Unread post by Sb919 »

Thank you for all the effort and time researching you are putting into this. I hope this works, or at least brings us closer to a fix.

I will be following closely, good luck!
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guacamo
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Re: Etiology of PSSD and potential treatment.

Unread post by guacamo »

I literally do nothing but research, your words of comfort mean to me a lot.
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Re: My theory - Etiology of PSSD and potential treatment.

Unread post by Frog »

I’ve changed the thread title to make clear that this is still all theoretical
Panax Ginseng, Lithium Orotate, Boron, Cordyceps, Tyrosine, Red Maca, Horny Goats Weed, Tribulus, Shilajit

U.K. members, please contact your MP and let me know!
sovietxrobot
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Re: My theory - Etiology of PSSD and potential treatment.

Unread post by sovietxrobot »

Its entirely plausible that 5HT2B is involved in PSSD, and definitely merits further investigation. Theres likely a constellation of receptors that are effected. Statements 1, 2, and 13 are too strongly worded. Buspirone is a front-line treatment for SSRI-induced dysfunction and its a partial agonist at 5HT1A. Dopamine agonists, precursors, and reuptake inhibitors certainly can help PSSD symptoms, many people benefit from wellbutrin, pramipexole, etc. Dopamine transmission is almost certainly part of the problem. The cognitive symptoms of PSSD mimic those of neuroleptic induced deficit syndrome, which is caused by antagonism of d2 receptors. I had severe cognitive symptoms that I completely reversed with wellbutrin + l-dopa. SJW and inositol certainly help some people but I have not seen any evidence that they have a greater success rate than any other drug (or chance, even).

I don't think any theory is complete without considering 5HT2A. Essentially all elements of SSRI sexual dysfunction have been linked to 5HT2A (and other in conjunction). 5HT2A is used as a model of sexual dysfunction because its strongly linked to premature/delayed ejaculation, which occur normally without SSRIs. It also controls dopamine efflux in various brain regions, which supports the idea of dopamine deficiency being a key facet of PSSD. Trazodone, a 5HT2A antagonist, has been used to treat SSRI-induced sexual dysfunction, albeit off-label. Again, personal anecdote, but trazodone has had probably the biggest impact on treating PSSD in my case- I saw great improvement in emotional range and depth, desire, genital sensivity, erection quality, and ejaculate volume while using trazodone.

I know nothing about calcium or magnesium in the brain, but I am very interested in any theory that explains why PSSD is so absurdly treatment resistant. Although I tried magnesium and it immediately worsened all of my symptoms. Another vexing problem to any unified theory of PSSD is how heterogeneous it is- everybody seems to react differently to everything.

I am looking forward to further discussion.
ryjoseph97
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Re: Etiology of PSSD and potential treatment.

Unread post by ryjoseph97 »

guacamo wrote: Wed Jul 14, 2021 2:46 pm I literally do nothing but research, your words of comfort mean to me a lot.
You add so much value to this community. I struggled a little to follow the post but I think I took away some important points. Do you think that the magnesium supplement needs to be L threonate? I’ve been taking magnesium chloride for about a week but I haven’t felt anything.
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guacamo
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Re: My theory - Etiology of PSSD and potential treatment.

Unread post by guacamo »

I do believe that magnesium l-threonate has the highest bioavailability from all of oral magnesiums, and specifically raises brain magnesium, compared to other magnesiums that raise it in the whole body, it is based on data but also by my personal experience. It can also be transdermal magnesium. Magnesium bioavailability and ability to replenish brain cellular magnesium vary a lot depending on the formula. The idea is to replenish brain magnesium in the fastest way possible so the treatment starts working right away. If you do not have access to the l threonate version then you may try chelate or citrate with higher doses, chloride may do the work too. For what it's worth i will do my trial with l threonate version and we may compare the results, if my way will work and your won't then you may just switch to l-threonate and everything will be fine. Did you take magnesium with inositol? And the second thing is did you experience brain fog? Because as far as i can tell the dose of magnesium should be high enough to induce mild brain fog, at least that was the case with PharmD who was cured by inositol. In my case magnesium l-threonate induces big brain fog. Direct quote from his success story, it happened at the same time he started recovering:

" 2. My memory has turned to crap. I can barely remember something I did 5 minutes ago. I have to check if I’ve turned off the iron 5 times before I leave the house. Just stupid little things that I NEVER ever used to think twice about.

3. My erections are much better than last update. I even get anticipatory erections before I open porn sites. Something I haven’t had in a while."
https://pssdlab.wordpress.com/pharmd-inositol/
link to the full recovery story

I suppose his memory problems were due to the magnesium, which blocks NMDA receptors that are pro-cognitive.
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Re: My theory - Etiology of PSSD and potential treatment.

Unread post by Truskawa »

Thank you for your input!
Very interesting theory.
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guacamo
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Re: My theory - Etiology of PSSD and potential treatment.

Unread post by guacamo »

sovietxrobot wrote: Wed Jul 14, 2021 4:57 pm Its entirely plausible that 5HT2B is involved in PSSD, and definitely merits further investigation. Theres likely a constellation of receptors that are effected. Statements 1, 2, and 13 are too strongly worded. Buspirone is a front-line treatment for SSRI-induced dysfunction and its a partial agonist at 5HT1A. Dopamine agonists, precursors, and reuptake inhibitors certainly can help PSSD symptoms, many people benefit from wellbutrin, pramipexole, etc. Dopamine transmission is almost certainly part of the problem. The cognitive symptoms of PSSD mimic those of neuroleptic induced deficit syndrome, which is caused by antagonism of d2 receptors. I had severe cognitive symptoms that I completely reversed with wellbutrin + l-dopa. SJW and inositol certainly help some people but I have not seen any evidence that they have a greater success rate than any other drug (or chance, even).

I don't think any theory is complete without considering 5HT2A. Essentially all elements of SSRI sexual dysfunction have been linked to 5HT2A (and other in conjunction). 5HT2A is used as a model of sexual dysfunction because its strongly linked to premature/delayed ejaculation, which occur normally without SSRIs. It also controls dopamine efflux in various brain regions, which supports the idea of dopamine deficiency being a key facet of PSSD. Trazodone, a 5HT2A antagonist, has been used to treat SSRI-induced sexual dysfunction, albeit off-label. Again, personal anecdote, but trazodone has had probably the biggest impact on treating PSSD in my case- I saw great improvement in emotional range and depth, desire, genital sensivity, erection quality, and ejaculate volume while using trazodone.

I know nothing about calcium or magnesium in the brain, but I am very interested in any theory that explains why PSSD is so absurdly treatment resistant. Although I tried magnesium and it immediately worsened all of my symptoms. Another vexing problem to any unified theory of PSSD is how heterogeneous it is- everybody seems to react differently to everything.

I am looking forward to further discussion.
1: for me it is clear that it is 5-HT1A postsynaptic receptor that is involved in sexual dysfunction in PSSD, but it cannot explain other symptoms that are also present in PSSD.
2: You can raise your dopamine to the level you will never achieve naturally and the relief it will produce will be mild at best (if any). I talk about pure dopamine increase without involving serotonin which happens with let's say amphetamine.
13. Inositol and SJW are the only supplements that produced more cured cases than 1.
5-HT2A, 5-HT2C, 5-HT3 and other serotonin receptors are very much involved in PSSD, the problem is they do not induce polyphasic reaction like 5-HT2B, which is involved in both serotonin reuptake and serotonin release. It is because of 5-HT2B receptor dysfunction that all postsynaptic receptors aren't activated and the effect they naturally exert in the body isn't present. PSSD symptoms vary between people because amount serotonergic neurons and serotonin receptors vary between individuals.
Sb919
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Re: My theory - Etiology of PSSD and potential treatment.

Unread post by Sb919 »

guacamo wrote: Wed Jul 14, 2021 5:18 pm Because as far as i can tell the dose of magnesium should be high enough to induce mild brain fog, at least that was the case with PharmD who was cured by inositol.
Not seeing a mention of magnesium in his trials. From what I'm reading, he added choline.
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