The best theory regarding PSSD.

This is for hypothesis and even educated speculation.
Neuroxam
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The best theory regarding PSSD.

Unread post by Neuroxam »

There are 3 serotonin receptors directly infuencing sexual behavior -5-HT1B, 5-HT1A, 5-HT2C
https://www.eurekaselect.com/55536/article
Knockout mice lacking the 5-HT1B gene have shown an increase in aggression and a higher preference for alcohol.[14] Under basal conditions, knockout mice present with a "normal" phenotype and exhibit a sucrose preference (lack of sucrose preference is considered a measure of anhedonia). However, after undergoing chronic unpredictable stress treatment to induce a "depression-like" phenotype these animals do not benefit from administration of selective serotonin reuptake inhibitor (SSRIs).[11]


Psychoneuroendocrinology. 2002 Jul;27(5):609-18.

Involvement of the 5-HT(1A) and 5-HT(1B) serotonergic receptor subtypes in sexual arousal in male mice.
Popova NK1, Amstislavskaya TG.
Author information

Abstract
The presence of a sexually receptive female behind a partition that prevents physical contact, but not seeing or smelling, increases blood testosterone level and induces the specific behavior in CBA male mice so that they more frequently approach the partition and spend more time near it in an attempt to make their way to the female. Treatment with the selective 5-HT(1A) serotonin receptor agonist 8-OH-DPAT (0.1, 0.25, 0.5 and 2.0 mg/kg) induced a dose-dependent decreasein the amount of time spent by the males near the partition, or "partition time", which is considered the main pattern of sexual motivation. The activating effect of female exposure on the male's pituitary-testicular system was totally blocked, as no increase in plasma testosterone level was observed. The 5-HT(1A) antagonist p-MPPI (0.1, 0.2 and 0.4 mg/kg) itself did not affect behavior or alter plasma testosterone, but attenuated the inhibiting effect of 8-OH-DPAT on behavior and totally antagonised the effect of the 5-HT(1A) agonist on testosterone response. The 5-HT(1B) agonist CGS-12066A (1.0 and 2.0 mg/kg) has no influence on the plasma testosterone increase exhibited by the male in response to female exposure. At the same time, either dose of CGS-12066A significantly reduced the partition time. The conclusion was made that the 5-HT(1A) subtype is involved in controlling both behavioral and hormonal indices of sexual arousal in male mice, while the 5-HT(1B) receptors antagonise sexual motivation, but do not modify the hypothalamic-pituitary-testicular response.

PMID: 11965359 [PubMed - indexed for MEDLINE]

My theory is that by inhibiting SERT, 5-HT1B and 5-HT1A autoreceptors downregulate, thus stop inhibiting serotonin flow to postsynaptic receptors, which ends up killing libido and also producing anhedonia

Basically 5-HT1B and 5-HT1A antagonist should in theory raise libido, while agonists should kill it.

Buspirone 5HT1A agonist downregulates autoreceptors, effect similar to SERT inhibitors. Using deductive reasoning 5-HT1A and 5-HT1B antagonists should in theory after few weeks (depending on affinity) upregulate autoreceptors, thus bringing back more normal flow of serotonin to the synapse.
tonyareias
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Re: The best theory regarding PSSD.

Unread post by tonyareias »

Binospirone is a drug which acts as a partial agonist at 5-HT1A somatodendritic autoreceptors but as an antagonist at postsynaptic 5-HT1A receptors. It has anxiolytic effects.

Buspirone acts as an agonist of the serotonin 5-HT1A receptor with high affinity. It is a preferential full agonist of presynaptic 5-HT1A receptors, which are inhibitory autoreceptors, and a partial agonist of postsynaptic 5-HT1A receptors.
Thomas
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Re: The best theory regarding PSSD.

Unread post by Thomas »

HereToHeal wrote: Sat Jul 04, 2020 10:54 am There is a study on that:

https://academic.oup.com/ijnp/article/12/8/1045/677907
This study on rats is 11 years old and seems promising. Was there any development on human beings?
Escitalopram, 10mg/day, Jan-May 2019. Fluoxetine, May-Sept 2019. Mirtazapine 7,5mg/day, November 2019-January 2020. Escitalopram, 5mg/day, Feb-May 2020.
Symptoms: sexual & emotional numbness
cdraham
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Re: The best theory regarding PSSD.

Unread post by cdraham »

Can you trial this?
Matthias66
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Re: The best theory regarding PSSD.

Unread post by Matthias66 »

It makes a lot of sense, and I've come to the same conclusion about the use of a 5HT1a antagonist, which should in effect send a message to the brain to not slow down the release of Serotonin, and eventually restore balance through upregulation.

The inherent difficulty is this- most 5HT1a antagonists are experimental drugs done in studies on rats or micw, or they are beta blockers with limited efficacy. Some of them are atypical antipsychotics, or used in other aspects than being able to be prescribed as medication. So unfortunately, due to all this, it is very hard to find anything that acts as a 5HT1a antagonist. Although CBG oil is looking very promising, although from what I have seen, it is a moderate 5HT1a antagonist. But with enough administration- it may be worth a try.
arahant
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Re: The best theory regarding PSSD.

Unread post by arahant »

Matthias66 wrote: Sun Sep 27, 2020 11:30 pm It makes a lot of sense, and I've come to the same conclusion about the use of a 5HT1a antagonist, which should in effect send a message to the brain to not slow down the release of Serotonin, and eventually restore balance through upregulation.

The inherent difficulty is this- most 5HT1a antagonists are experimental drugs done in studies on rats or micw, or they are beta blockers with limited efficacy. Some of them are atypical antipsychotics, or used in other aspects than being able to be prescribed as medication. So unfortunately, due to all this, it is very hard to find anything that acts as a 5HT1a antagonist. Although CBG oil is looking very promising, although from what I have seen, it is a moderate 5HT1a antagonist. But with enough administration- it may be worth a try.
Not a lot of sense, 5HT1a agonists are pro-sexual because they reduce serotonin via negative feedback. Its function is signaling the "absorption" of serotonin by its receptors.
It is not as simple as naive thinking that "agonist" always "increase" and "antagonist" always "decrease."

So that this paper:
Pharmacological Studies on the Role of 5-HT1A Receptors in Male Sexual Behavior of Wildtype and Serotonin Transporter Knockout Rats
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136541/

Showed that 5-HT1A receptor antagonists can fully antagonize the pro-sexual effect of 5-HT1A receptor agonists.
The prototypal 5-HT1A receptor agonist (±) or (+)-8-OH-DPAT, a non-selective auto-receptor and heteroreceptor agonist (Larsson et al., 1990), has strong and dose-dependent pro-sexual effects (Mos et al., 1991; Chan et al., 2011; Snoeren et al., 2014). This pro-sexual effect can be fully antagonized by the 5-HT1A receptor antagonist WAY100,635, a behaviorally silent compound (de Jong and Neumann, 2015).
The user Tour_IS on reddit summarized the mechanisms in just a few paragraphs:

https://www.reddit.com/r/pharmacy/comme ... ri_vs_cbd/

Buspirone reduces anxiety by signaling for reducing serotonin (which is an anxiogenic monoamine).
SSRI floods the brain with too much serotonin that downregulates serotonin receptors responsible for signaling "fear, anxiety" and sexual drive, and this downregulation is not immediate, which explains the delayed onset of response on SSRIs, usually in a few weeks.
Wellbutrin (2007 - 2018)
Wellbutrin + Sertraline (2015)
Wellbutrin + Ritalin (2016 - 2018)
Wellbutrin + Ritalin + Sertraline (3 months in 2018)
Buspirone (Feb 2019 - Today)
Ritalin + Buspirone (Nov 2019 - today)
Matthias66
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Re: The best theory regarding PSSD.

Unread post by Matthias66 »

arahant wrote: Sun Sep 27, 2020 11:59 pm
Matthias66 wrote: Sun Sep 27, 2020 11:30 pm It makes a lot of sense, and I've come to the same conclusion about the use of a 5HT1a antagonist, which should in effect send a message to the brain to not slow down the release of Serotonin, and eventually restore balance through upregulation.

The inherent difficulty is this- most 5HT1a antagonists are experimental drugs done in studies on rats or micw, or they are beta blockers with limited efficacy. Some of them are atypical antipsychotics, or used in other aspects than being able to be prescribed as medication. So unfortunately, due to all this, it is very hard to find anything that acts as a 5HT1a antagonist. Although CBG oil is looking very promising, although from what I have seen, it is a moderate 5HT1a antagonist. But with enough administration- it may be worth a try.
Not a lot of sense, 5HT1a agonists are pro-sexual because they reduce serotonin via negative feedback. Its function is signaling the "absorption" of serotonin by its receptors.
It is not as simple as naive thinking that "agonist" always "increase" and "antagonist" always "decrease."

So that this paper:
Pharmacological Studies on the Role of 5-HT1A Receptors in Male Sexual Behavior of Wildtype and Serotonin Transporter Knockout Rats
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136541/

Showed that 5-HT1A receptor antagonists can fully antagonize the pro-sexual effect of 5-HT1A receptor agonists.
The prototypal 5-HT1A receptor agonist (±) or (+)-8-OH-DPAT, a non-selective auto-receptor and heteroreceptor agonist (Larsson et al., 1990), has strong and dose-dependent pro-sexual effects (Mos et al., 1991; Chan et al., 2011; Snoeren et al., 2014). This pro-sexual effect can be fully antagonized by the 5-HT1A receptor antagonist WAY100,635, a behaviorally silent compound (de Jong and Neumann, 2015).
The user Tour_IS on reddit summarized the mechanisms in just a few paragraphs:

https://www.reddit.com/r/pharmacy/comme ... ri_vs_cbd/

Buspirone reduces anxiety by signaling for reducing serotonin (which is an anxiogenic monoamine).
SSRI floods the brain with too much serotonin that downregulates serotonin receptors responsible for signaling "fear, anxiety" and sexual drive, and this downregulation is not immediate, which explains the delayed onset of response on SSRIs, usually in a few weeks.
So what you are saying, in another words, is that by using an 5HT1a agonist, you are activating a 5HT1a receptors, which sends a message to the Dorsal Raphe Nucleus in the brain, to slow down on the release of Serotonin in the Postsynaptic Serotonin neuron? Isn't the whole commonly accepted theory in regards to PSSD is the desensitization of presynaptic 5HT1a receptors in the brain, coupled with SERT malfunctions? While in a sense, it does mean temporarily activating 5HT1a receptors Presynaptic, which would send a message to the brain to slow up on the release of Serotonin, the effect is only temporary.

A lot of people on this forum talk about how Buspirone is effective for a little bit and stops working, or other things as well. But the effect is temporary. But if you can block those Presynaptic 5HT1a receptors, would that not send a message to the brain to completely ease up on Serotonin release? Or would it tell the brain to release more Serotonin?

From what I've read from users' experiences, 5HT1a agonists' effects are very temporary. The main issue is that the 5HT1a autoreceptors have been desensitized/switched to the "off" position. The goal is to resensitize them. I don't know if constant hitting of those receptors with an agonist will resensitize them, and according to my reading, antagonists seem to reverse the issues. It is illogical, it doesn't make sense, but I think it is worth looking into:

https://www.researchgate.net/publicatio ... on_in_rats

https://pssdlab.wordpress.com/5-ht1a-de ... on-theory/

"In this manner, 5-HT1A autoreceptors work as an effective regulator of 5-HT levels in the brain (Bang et al., 2012). Decreased 5-HT transmission has long been associated with MDD (Van Praag et al. 1970) and it is thought that the RN is where SSRI antidepressants exhibit their therapeutic effects. It then comes as little surprise that the 5-HT1A has been heavily implicated in effective clinical treatment of depression and anxiety. SSRIs are believed to block 5-HT reuptake by binding to SERT (5-HTT) and reducing its reuptake abilities (Murphy et al., 2004). If this was the only result, increased somatodendritic and terminal autoreceptor binding would inhibit release of 5-HT into the synapse: Resulting in no increased 5-HT levels. Through a process that is still unknown, serotonin transmission is eventually enhanced by “desensitization” of both the somatodendritic and terminal autoreceptors (Chaput et al., 1985), allowing synaptic 5-HT to accumulate in the synapse. This accounts for the characteristic 4-8 week delay between treatment origins and therapeutic relief (Gartside et al., 1995; Blier, 2010; Richardson-Jones et al., 2010). 5-HT and 5-HT1A agonist binding on the presynaptic autoreceptor inhibits 5-HT activity by hyperpolarizing the neuronal membrane (Penington and Fox, 1994).

Presynaptic 5-HT1A receptors are preferentially desensitized by chronic SSRI treatment while postsynaptic receptors are not (Pineyro and Blier, 1999). This preferential presynaptic desensitization is also seen after chronic administration of 5-HT1A agonists (Blier and de Montigny, 1994). 5-HT1B/1D autoreceptor agonists have shown less inhibitory action in cells treated chronically with low dose Fluvoxamine (Blier and de Montigny, 1983).
arahant
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Re: The best theory regarding PSSD.

Unread post by arahant »

A lot of people on this forum talk about how Buspirone is effective for a little bit and stops working
That's not what happened to me, and I am more than 1.5 year taking it.

Now, given that you decided to mix forum reports with publications. Which report do you consider valid?

The publication I cited:
Pharmacological Studies on the Role of 5-HT1A Receptors in Male Sexual Behavior of Wildtype and Serotonin Transporter Knockout Rats
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136541/
Was just to show that a experiment proved that these 5-HT1A agonists are pro-sexual and anxiolytic. And 5HT1A antagonists reversed the pro-sexual effects.

Now regarding going into pure speculation:
5HT1a receptors Presynaptic, which would send a message to the brain to slow up on the release of Serotonin, the effect is only temporary.
SSRIs act to prevent serotonin reuptake into the cell. Increased serotonin in synapse leads to increased signaling which can then lead to downregulation of postsynaptic 5HT1A receptors over weeks and the therapeutic effect of SSRIs.
Maybe staying long term on 5HT1a agonists puts the brain in a "low serotonin" scenario for enough time that the buspirone neurogenic effect upregulates 5HT1a .

More about neurogenesis:

"An exploratory study of combination buspirone and melatonin SR in Major Depressive Disorder (MDD): A possible role for neurogenesis in drug discovery"
https://www.sciencedirect.com/science/a ... 5612002464

Publication showing the first time neurogenesis was proven in mammals on 5HT1a agonists:
"The partial 5-HT1A receptor agonist buspirone enhances neurogenesis in the opossum (Monodelphis domestic)"
https://www.sciencedirect.com/science/a ... via%3Dihub
How much time/dose is needed to have its effects in humans? One pill, one week, one month, one year?

No one knows, but it's unlikely to be just a few pills/months on stable doses.
Wellbutrin (2007 - 2018)
Wellbutrin + Sertraline (2015)
Wellbutrin + Ritalin (2016 - 2018)
Wellbutrin + Ritalin + Sertraline (3 months in 2018)
Buspirone (Feb 2019 - Today)
Ritalin + Buspirone (Nov 2019 - today)
Matthias66
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Re: The best theory regarding PSSD.

Unread post by Matthias66 »

arahant wrote: Fri Oct 02, 2020 7:43 pm
A lot of people on this forum talk about how Buspirone is effective for a little bit and stops working
That's not what happened to me, and I am more than 1.5 year taking it.

Now, given that you decided to mix forum reports with publications. Which report do you consider valid?

The publication I cited:
Pharmacological Studies on the Role of 5-HT1A Receptors in Male Sexual Behavior of Wildtype and Serotonin Transporter Knockout Rats
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136541/
Was just to show that a experiment proved that these 5-HT1A agonists are pro-sexual and anxiolytic. And 5HT1A antagonists reversed the pro-sexual effects.

Now regarding going into pure speculation:
5HT1a receptors Presynaptic, which would send a message to the brain to slow up on the release of Serotonin, the effect is only temporary.
SSRIs act to prevent serotonin reuptake into the cell. Increased serotonin in synapse leads to increased signaling which can then lead to downregulation of postsynaptic 5HT1A receptors over weeks and the therapeutic effect of SSRIs.
Maybe staying long term on 5HT1a agonists puts the brain in a "low serotonin" scenario for enough time that the buspirone neurogenic effect upregulates 5HT1a .

More about neurogenesis:

"An exploratory study of combination buspirone and melatonin SR in Major Depressive Disorder (MDD): A possible role for neurogenesis in drug discovery"
https://www.sciencedirect.com/science/a ... 5612002464

Publication showing the first time neurogenesis was proven in mammals on 5HT1a agonists:
"The partial 5-HT1A receptor agonist buspirone enhances neurogenesis in the opossum (Monodelphis domestic)"
https://www.sciencedirect.com/science/a ... via%3Dihub
How much time/dose is needed to have its effects in humans? One pill, one week, one month, one year?

No one knows, but it's unlikely to be just a few pills/months on stable doses.
I have thought about what you said, and I get the idea of what you are saying, but one article doesn't convince me of the pro-sexual side effects of agonists. There are 7 known 5HT receptors in the human body,
and for example, in with the process of ejaculation, 5HT2C increases erections, but delays ejaculation, whereas 5HT1A basically inhibits erections. So there are some serotonin effects in ejaculation- primarily
afterwards and with 5HT2C, but not with 5HT1A.

The whole issue with the desensitization of 5HT1A receptors is that they have constantly been hit by trapped Serotonin when someone was on an antidepressant and when they got off, these 5HT1A receptors became
desensitized. When you look at receptor desensitization in any other type of cell model- desensitization happens when a cell or neuron no longer becomes "sensitive". Sensitivity of a cell happens when you have multiple
receptor sites for a chemical to interact with, causing a greater action potential for the cell to activate. When a cell becomes desensitized, it has a lot less receptor sites, which means a lot less sensitivity. The only way
to fix this is by upregulation, and it seems the way to do this is through an antagonist, which with create more receptor sites, and eventually lead to upregulation.

The problem with the idea of constant agonism is that the neuron has become desensitized with fewer receptor sites, and hitting those few receptor sites won't lead to a higher action potential. It is like a toll both- if you
have one toll booth and a long line of traffic- it isn't very efficient and it will be slow traffic wise to take care of everyone one at a time. But if you have multiple toll booth stations, you are about to get a lot more people
through, after paying the toll, and the traffic will be a lot less worse than just having one toll booth that everyone goes through.

There has to be more receptor sites on a cell that can interact with a stimuli to be "sensitive" again. We know that antidepressants basically shut down a lot of receptor sites because there is so much available Serotonin that
it doesn't need a bunch of receptor sites to go through to get stimulated- initially. Antagonism has worked with rats and mice, and from a cell standpoint, in regards to downregulation and upregulation, it makes perfect sense.

The hope that an agonist that doesn't have the same weight and power of an SSRI will eventually resensitize desensitized neurons doesn't make sense to me.
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