I am going to drop a major bomb soon

[arahant]

I'm neurologist but many of my patients have SSRI (not from me!!). Now I don't prescribe SSRI under 65 years old and I use Vortioxetine always

Good to know. And the evidence for SSRIs is much better in elderly than young ppl where placebo effect seems to be strong.

[ErgogenicHealth]

Hey man,

Thanks for starting this thread.

You are really helping the community.

What you discuss about SJW makes sense to me, but confuses me even more about Cyproheptadine.

Cyproheptadine, being a 1A antagonist makes me WORSE for days, but then is followed by this amazing snap back effect 4 days later, which works every single fkn time without question... However, this will only then last about 5-7 days before "numbing up" again.

I recently established that Taurine may also worsen my symptoms.

SJW will induce a window after 3-4 days of back to back dosing for me... So what might this say about my response to lithium? I have not tried lithium due to fear of yet another crash.

I had windows on ALCAR (1A agonist), which I did use chronically for years.

[guacamo]

Thanks for posting the theory, it is good to see it triggers a further discussion instantly. The community needs this.
I am a bit surprised with some points however, for instance sjw was mentioned to be a (post?)5ht1a agonist. The research on sjw is quite messy, but one of its main effects is post 5ht1a upregulation, and afaik limited impact on the autoreceptor.
I am also not entirely clear how some of the crashes seen here, that occur from post 5ht1a activation/agonism (and i assume downregulation soon after) fit your theory?
Finally, how do you see buspirone in this? (Autoreceptor agonist, doesnt do much for most but did give some people relief, sometimes in combination with prozac)

Hey, i do have an access to the paper with the whole "5-HT1A upregulation and St John Wort" and in this paper they mention that SJW upregulates pre-synaptic 5-HT1A, there was no mention of post-synaptic 5-HT1A at all.
https://imgur.com/a/QRwAX9A fragment of the mentioned paper
About buspirone and other farmaceutical 5-HT1A agonists, i still yet have to answer the question why 5-HT1A agonists do cure pssd and what mechanism is there. I have several ideas but it's too early to publish them.
@up
Listen, buspirone does not stop magically acting at pre-synaptic 5-HT1A when you exceed the 30mg dose, it may start to act at post-synaptic receptor at this dose, but i do not think the information from wikipedia is correct there, as i wrote in the main post F-15599 is 5-HT1A agonist, yet it does stimulate 5-HT1A post-synaptic receptor at low doses, and switches to 5-HT1A autoreceptor at higher doses, it is in conflict with the information in wikipedia that states:

For this reason, 5-HT1A receptor agonists tend to exert a biphasic mode of action; they decrease serotonin release and postsynaptic 5-HT1A receptor activity in low doses, and further decrease serotonin release but increase postsynaptic 5-HT1A receptor activity at higher doses by directly stimulating the receptors in place of serotonin.

The changes can be because 5-HT1A autoreceptor actually start working closer to normal, not because post-synaptic 5-HT1A eventually become activated.
But let's see where it takes us if we follow this way of thinking.
Let's pretend that average person with normal sensitivity to the both types of 5-HT1A receptor is (let's give it arbitrary number) around 60% for autoreceptor and 30% for post-synaptic receptor and the growth is linear.
Then 10mg of buspirone increases activity of both by 10 percent.
at 30mg you have 70% on autoreceptor and 60% on post-synaptic receptor, notice that post-synaptic receptor activity increased 100%, compared to 40% increase of pre-synaptic receptor. Reverse this and assume that in PSSD suferrers it is 10% activity of pre-synaptic receptor and 30% of post-synaptic, at 30mg you have 40% activity of pre-synaptic (300% increase) and 60% of post-synaptic (100% increase). I do know that the growth is not linear and the percentages are arbitrary, but this just a thought experiment to show what might be the difference between PSSD sufferers and non-PSSD people, because as we know in PSSD people have paradoxical reaction to serotonin drugs and 5-HT1A stimulation.

No one claimed "stopping magically" to be pre after 30 mg dose, and such a thing, unit step functions, is only seen in abstract math with some applications on digital signal processing:


And it is unlikely to be seen in biological systems.

I am not sure if you overcomplicate it on purpose or what, like putting all those random percentages out of nowhere.

There's a good practice in scientific writing that says like "one good graph can explain much more than trying to put those numbers on a paragraph".

There's a simple dose-response graph that I have already posted above:



Which is more realistic, and it looks like a smoothed "step function", commonly approximated by sigmoid, hyperbolic tangents, etc...

It can be described as having a "toe", linear region, and a "shoulder", and the tricky part is finding the "optimal dose" on that curve.

The most complete description of such a mechanism I found here, including a bit about Lithium:

http://www.pni.org/neuropsychiatry/aggr ... buspirone/

And it also implies in secondary antagonism of 2A

"In high doses, buspirone acts as a moderate but incomplete serotonin 1A agonist. The differentiation of pre-synaptic and post-synaptic effects has been argued to be appropriately modeled on such features as pre-synaptic hypothermia and post-synaptic elevations of prolactin which can be blocked by serotonin antagonist type drugs. 125, 126, 127, 128 Post-synaptic agonism may well imply some kind of reciprocal relationship with serotonin 2, implying again a serotonin 2 antagonism, using a variety of models, namely model of hypo/hyperthermia, hypotension / hypertension 129, quipazine related effects, habituation of tactile startle via actions at 5-HT2 receptors 125, 130, 131 and even migraine 132 "

I recomend you to look at one of the papers i link in the main post about 5-HT1A and depression anxiety, i know it is only 1 paper so we should suspend judgement or be at least a bit cinical as this behavior should exist in every research, because from personal experience after fact checking papers I am just very surpised that a lot of them are just incorrect at their core or the study was done poorly, or the main conlcusion is different than what the experiment state. I am deeply concerned about it and i cannot understand that people who devote their life to science are often so incopetent that when reading every study you have to fact check everything, like in every study that refer to the famous paper on this forum "st john wort and upregulation of 5-HT1A" they say that sjw upregulate post-synaptic receptor when the study does not mention post-synaptic expression and clearly state on first or second page that they did check pre-synaptic expression. I mean how you can be a so incopetent? I digressed hard. Anyway i recommend you to look at the study as it says that post-synaptic receptor is anxiety inducing, however mice with overexpressed post-synaptic 5-HT1A have high anxiety, but perform better at forced swimming test. If post-synaptic receptor is the one that is malfuctioning then lithium should be helping people and as we know it does not or does very little and it's effects are inconsistent among peoplw. There are many studies on SSRI and post-synaptic sensitivity and expression and they say that post-synaptic receptor does not respond with reducing sensitivity or downregulation, in contrast to pre-synaptic receptor that is both downregulating and reducing sensitivity with SSRI treatment.

[Thomas]

Could you please add scientific papers in your OP to back up your theory (every "bold" statement)? Thanks

SJW -serotonin reuptake inhibition without affecting SERT, 5-HT1A agonist

Especially this one. I have only read the opposite (i.e. SJW affects SERT), for instance here: https://unisciencepub.com/storage/2021/ ... tivity.pdf
This is why I discarded SJW as a treatment so far.

[Thomas]

It's more that serotonin inhibit ejaculation.
Since I have PSSD I asked to every patient I seel Wich take SSRI about their sexual life. Genital numbness, anesthesia is very uncommon.

Check this paper by Healy, chapter B.1. and its sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004927/
I am not sure whether this is "uncommon" or "usually imperceptible". Maybe we just feel what others don't.

In 1,5 years I diagnosed 2 PSSD, of course if I was sensibilised to this desease I would have committed the error to say it's psychologic and it will get better soon (like 99% of others doctors)

It would be interesting for you to gather some statistics, such as:
- PSSD cases
- sexual dysfunction after withdrawal
- anhedonia after withdrawal
- insomnia after withdrawal
etc.
/ number of people having stopped SSRIs (slowly or cold turkey)

As you are not specialized in PSSD, your statistics are not biased (yet)

[PsychoGenesis]

got sources for the claim that mdma is a reuptake "inverter" and not just inhibitor + releaser

potentially dangerous assumption

[cdraham]

Hey, i do have an access to the paper with the whole "5-HT1A upregulation and St John Wort" and in this paper they mention that SJW upregulates pre-synaptic 5-HT1A, there was no mention of post-synaptic 5-HT1A at all.
https://imgur.com/a/QRwAX9A fragment of the mentioned paper
About buspirone and other farmaceutical 5-HT1A agonists, i still yet have to answer the question why 5-HT1A agonists do cure pssd and what mechanism is there. I have several ideas but it's too early to publish them.
@up
Listen, buspirone does not stop magically acting at pre-synaptic 5-HT1A when you exceed the 30mg dose, it may start to act at post-synaptic receptor at this dose, but i do not think the information from wikipedia is correct there, as i wrote in the main post F-15599 is 5-HT1A agonist, yet it does stimulate 5-HT1A post-synaptic receptor at low doses, and switches to 5-HT1A autoreceptor at higher doses, it is in conflict with the information in wikipedia that states:
The changes can be because 5-HT1A autoreceptor actually start working closer to normal, not because post-synaptic 5-HT1A eventually become activated.
But let's see where it takes us if we follow this way of thinking.
Let's pretend that average person with normal sensitivity to the both types of 5-HT1A receptor is (let's give it arbitrary number) around 60% for autoreceptor and 30% for post-synaptic receptor and the growth is linear.
Then 10mg of buspirone increases activity of both by 10 percent.
at 30mg you have 70% on autoreceptor and 60% on post-synaptic receptor, notice that post-synaptic receptor activity increased 100%, compared to 40% increase of pre-synaptic receptor. Reverse this and assume that in PSSD suferrers it is 10% activity of pre-synaptic receptor and 30% of post-synaptic, at 30mg you have 40% activity of pre-synaptic (300% increase) and 60% of post-synaptic (100% increase). I do know that the growth is not linear and the percentages are arbitrary, but this just a thought experiment to show what might be the difference between PSSD sufferers and non-PSSD people, because as we know in PSSD people have paradoxical reaction to serotonin drugs and 5-HT1A stimulation.

No one claimed "stopping magically" to be pre after 30 mg dose, and such a thing, unit step functions, is only seen in abstract math with some applications on digital signal processing:


And it is unlikely to be seen in biological systems.

I am not sure if you overcomplicate it on purpose or what, like putting all those random percentages out of nowhere.

There's a good practice in scientific writing that says like "one good graph can explain much more than trying to put those numbers on a paragraph".

There's a simple dose-response graph that I have already posted above:



Which is more realistic, and it looks like a smoothed "step function", commonly approximated by sigmoid, hyperbolic tangents, etc...

It can be described as having a "toe", linear region, and a "shoulder", and the tricky part is finding the "optimal dose" on that curve.

The most complete description of such a mechanism I found here, including a bit about Lithium:

http://www.pni.org/neuropsychiatry/aggr ... buspirone/

And it also implies in secondary antagonism of 2A

"In high doses, buspirone acts as a moderate but incomplete serotonin 1A agonist. The differentiation of pre-synaptic and post-synaptic effects has been argued to be appropriately modeled on such features as pre-synaptic hypothermia and post-synaptic elevations of prolactin which can be blocked by serotonin antagonist type drugs. 125, 126, 127, 128 Post-synaptic agonism may well imply some kind of reciprocal relationship with serotonin 2, implying again a serotonin 2 antagonism, using a variety of models, namely model of hypo/hyperthermia, hypotension / hypertension 129, quipazine related effects, habituation of tactile startle via actions at 5-HT2 receptors 125, 130, 131 and even migraine 132 "

I recomend you to look at one of the papers i link in the main post about 5-HT1A and depression anxiety, i know it is only 1 paper so we should suspend judgement or be at least a bit cinical as this behavior should exist in every research, because from personal experience after fact checking papers I am just very surpised that a lot of them are just incorrect at their core or the study was done poorly, or the main conlcusion is different than what the experiment state. I am deeply concerned about it and i cannot understand that people who devote their life to science are often so incopetent that when reading every study you have to fact check everything, like in every study that refer to the famous paper on this forum "st john wort and upregulation of 5-HT1A" they say that sjw upregulate post-synaptic receptor when the study does not mention post-synaptic expression and clearly state on first or second page that they did check pre-synaptic expression. I mean how you can be a so incopetent? I digressed hard. Anyway i recommend you to look at the study as it says that post-synaptic receptor is anxiety inducing, however mice with overexpressed post-synaptic 5-HT1A have high anxiety, but perform better at forced swimming test. If post-synaptic receptor is the one that is malfuctioning then lithium should be helping people and as we know it does not or does very little and it's effects are inconsistent among peoplw. There are many studies on SSRI and post-synaptic sensitivity and expression and they say that post-synaptic receptor does not respond with reducing sensitivity or downregulation, in contrast to pre-synaptic receptor that is both downregulating and reducing sensitivity with SSRI treatment.

Dxm gave me biggest emotional window out of anything so far - why do you think does this happen? Its sigma agonism controls 5ht7c,maybe it's that?

[MindChanger]

DXM nay have an influence on 5HT1A (not sure whether presynaptic tho) or at least its G-coupled protein.

"A high dose of DM significantly produced serotonin syndrome in mice. In addition, treatment with DM resulted in a significant increase in 5-HT1A receptor mRNA expression" (https://academic.oup.com/ijnp/article/1 ... 49/2946757).

"These results suggest that DM may inhibit the G-protein coupled inwardly rectifying K(+) channels" (https://pubmed.ncbi.nlm.nih.gov/10974313/).

But it is too dirty to know for sure.

[cdraham]

DXM nay have an influence on 5HT1A (not sure whether presynaptic tho) or at least its G-coupled protein.

"A high dose of DM significantly produced serotonin syndrome in mice. In addition, treatment with DM resulted in a significant increase in 5-HT1A receptor mRNA expression" (https://academic.oup.com/ijnp/article/1 ... 49/2946757).

"These results suggest that DM may inhibit the G-protein coupled inwardly rectifying K(+) channels" (https://pubmed.ncbi.nlm.nih.gov/10974313/).

But it is too dirty to know for sure.

Yes, sigma agonism also looks interesting, bc it regulates serotonin receptors.

[heymartinn]

DXM nay have an influence on 5HT1A (not sure whether presynaptic tho) or at least its G-coupled protein.

"A high dose of DM significantly produced serotonin syndrome in mice. In addition, treatment with DM resulted in a significant increase in 5-HT1A receptor mRNA expression" (https://academic.oup.com/ijnp/article/1 ... 49/2946757).

"These results suggest that DM may inhibit the G-protein coupled inwardly rectifying K(+) channels" (https://pubmed.ncbi.nlm.nih.gov/10974313/).

But it is too dirty to know for sure.

Yes, sigma agonism also looks interesting, bc it regulates serotonin receptors.

What's your guys thoughts on fenclonine? In theory, wouldn't lowering serotonin for at least 4 weeks would result in pre-synaptic upregulation? or any other positive un-doing of what SSRI's has done?