PSSD could be a mitochondrial disorder

This is for hypothesis and even educated speculation.
cdraham
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PSSD could be a mitochondrial disorder

Unread post by cdraham »

Hello,

I have severe PSSD for more than 1.5 years and after doing alot of reading I think at the core of PSSD there is mitochondrial dysfunction. I've been in contact with neuroscientists, etc. over twitter and weve been exchanging ideas how this could have happened.

SSRI's have been found to disrupt mitochondrial function:

https://pubmed.ncbi.nlm.nih.gov/18344530/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777788/

"In human hepatocytes that express cytochrome P450, isoform 3A4, after 24 h exposure, nefazodone and trazodone collapsed mitochondrial membrane potential, and imposed oxidative stress, as detected via glutathione depletion, leading to cell death. "

When this mitochondrial dysfunction happens, oxidative/inflammatory cascades could lead to epigenetic changes of the androgen receptor:

https://www.sciencedirect.com/science/a ... 5618300139

"ATZ caused transcriptional repression of the spermatogenesis-related genes SRD5A2 and CFTR, the antioxidant defense genes SOD2 and GPX4B, and the DNA repair gene XPC"

(ATZ is not SSRIS but disrupted the same mitochondrial membranes as SSRIs did)

Crosstalk between mitochondria and androgens:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922316/

Sex Hormones and Mitochondria:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725410/

The ATZ link

I've taken a closer look at the herbicide Atrazine and found something very interesting. First, it seems to induce mitochindrial damage:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1853311/
https://pubmed.ncbi.nlm.nih.gov/29865786/

Finasteride ist linked to breast cancer:
https://www.sciencedirect.com/science/a ... 261300081X

Finasteride and Insulin resistance:
https://pubmed.ncbi.nlm.nih.gov/25460297/

Finasteride and Kidney failure (due to low ATP maybe?) or oxidative stress
https://pubmed.ncbi.nlm.nih.gov/31100850/

Atrazine can lead to increased breast cancer risk, insulin resistance, like other endocrine disrupters it is toxic to marine life:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179673/
https://pubmed.ncbi.nlm.nih.gov/19365547/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198780/
https://pubmed.ncbi.nlm.nih.gov/18941967/

We know in Post Finasteride Syndrome SRD5A2 is methylated:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652249/

Now what happens when the mitochondria is dysfunctional? Not enough ATP is produced. ATP is the energy source of cells and it is required for receptors to function. It is involved in many functions of the body. For example the glymphatic system, the waste detox system of the brain, is highly dependent on ATP. Many of us suffer from unrefreshing sleep so my thought was this system could be impaired by this too.

Then there is the big question, if it is mitochondrial dysfunction why are other tissues/organs not affected? I think the answer here lies in the different affinities in the CNS of SSRI's/Finasteride. Here trazodone led to oxidative stress in the testicles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087606/

The itself brain is particularly sensitive to mitochondrial dysfunction as a result of its high metabolic demand.

Another thing that can happen as consequence of mitochondrial dysfunction is neuroinflammation: https://www.sciencedirect.com/science/a ... 4910001029

Neuroinflammation was linked to Tinnitus, Head Pressure, TRP sensory system disruption
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581239/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057689/
https://www.frontiersin.org/research-to ... d-immunity


The tamoxifen link


Tamoxifen can induce a similiar syndrome to PFS/PSSD, https://www.urmc.rochester.edu/news/sto ... e-antidote

Tamoxifen negatively affected the mitochondria: https://cancerres.aacrjournals.org/content/67/3/1282

There is more to this, I'm currently reading more about it.

Improvements


Many of us suffer from chronic fatigue and muscle weakness, I used to be a regular gym visitor and as supplement I used creatine, before PSSD I never noticed direct benefits from it, last year with PSSD I noticed I felt significantly stronger in the gym from creatine. My thought was the creatine increased the ATP (at least systemic) and led to improvements of cell function.

Edit: Also some here got improvements from HBOT (Hyperbaric Oxygen), which leads to decreased mitochondrial oxidative stress after repeated use, from what I know. The member driksdog improved on ozone therapy, which modulates oxidative stress: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943601/

Something I also saw many PFS sufferes improved on sodium butyrate, which could have been because butyrate enhances mitochondrial function during oxidative stress: https://www.nature.com/articles/s41398-017-0089-z

The member Joshi here who has PSSD improved on this bacteria strain: Clostridium butyricum, it produces butyrate in the gut. https://pubmed.ncbi.nlm.nih.gov/31734354/

Other dysfunctions in PSSD


In addition to this, we might suffer from LTP impairment in the hippocampus: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214920/

Edit2:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725410/

Added this important study.

"Since few years, there is a growing interest in the effects of sex steroids on brain mitochondrial metabolism. While the mitochondrial effects of testosterone are not well documented, several pharmacological studies have shown that exogenous administration of 17β-estradiol and/or progesterone increases RC function and decreases oxidative stress in brain mitochondria"

This is what they found in the CSF of PFS patients (taken from Melcangis study): https://i.imgur.com/6QtCQUM.png

Low allopregnanolone itself can lead to mitochondrial dysfunction, inflammation, HPA axis disruption

-> Is this why some PFS suffers improve from Progesterone?

"Interestingly, the age-induced decline in mitochondrial function could modify sex steroid levels on its own. Thus, mitochondria are not only the targets of sex steroid actions but also the site of the initial steps of steroidogenesis."

-> Is this where the neurosteroids deficit in PFS stems from?

Edit3:

Venlafaxine is an opioid and nmda antagonist: https://www.martincwiner.com/venlafaxin ... ty-debate/
https://medicalxpress.com/news/2020-08- ... users.html

Excessive Activation of NMDA Receptors
in the Pathogenesis of Multiple Peripheral Organs via Mitochondrial Dysfunction, Oxidative Stress, and Inflammation: https://link.springer.com/content/pdf/1 ... 0298-w.pdf

Withdrawing from this would lead to a inflammation / glutamate storm, mitochondrial damage would even amplify this turns into a never ending cycle.

Why do some only get sexual symptoms while others get the full PSSD syndrome?

It happens because of different genetics, different levels of resilience in different areas. How exactly the libido gets destroyed may have to do with the down stream hormone effects of allopregnanolone.

I think this is because some people are more susceptible to low allopregnanolone than others, even with the same degree of mitochondrial damage. More severe mitochondrial damage would cause more more neuroinflammation than mild mitochondrial damage and low allopregnanolone, explaining why some people only get libido problems but not the really bad fatigue and cognitive problems.

Allopregnanolone itself is anti-inflammatory, but can never lead to as bad neuroinflammation as severe mitochondrial damage: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042158/
Last edited by cdraham on Tue Aug 18, 2020 9:20 am, edited 16 times in total.
HereToHeal
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Re: PSSD as mitochondrial disorder

Unread post by HereToHeal »

Kpavel had a similar theory. He took a stack of supplements and seemed to have getting good results.
You should get him involved in your research.
JP1985
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Re: PSSD as mitochondrial disorder

Unread post by JP1985 »

cdraham wrote: Wed Aug 12, 2020 10:08 am Hello,

I have severe PSSD for more than 1.5 years and after doing alot of reading I think at the core of PSSD there is mitochondrial dysfunction. I've been in contact with neuroscientists, etc. over twitter and weve been exchanging ideas how this could have happened.

SSRI's have been found to disrupt mitochondrial function:

https://pubmed.ncbi.nlm.nih.gov/18344530/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777788/

"In human hepatocytes that express cytochrome P450, isoform 3A4, after 24 h exposure, nefazodone and trazodone collapsed mitochondrial membrane potential, and imposed oxidative stress, as detected via glutathione depletion, leading to cell death. "

When this mitochondrial dysfunction happens, oxidative/inflammatory cascades could lead to epigenetic changes of the androgen receptor:

https://www.sciencedirect.com/science/a ... 5618300139

"ATZ caused transcriptional repression of the spermatogenesis-related genes SRD5A2 and CFTR, the antioxidant defense genes SOD2 and GPX4B, and the DNA repair gene XPC"

(ATZ is not SSRIS but disrupted the same mitochondrial membranes as SSRIs did)

Crosstalk between mitochondria and androgens:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922316/

We know in Post Finasteride Syndrome SRD5A2 is methylated:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652249/

Now what happens when the mitochondria is dysfunctional? Not enough ATP is produced. ATP is the energy source of cells and it is required for receptors to function. It is involved in many functions of the body. For example the glymphatic system, the waste detox system of the brain, is highly dependent on ATP. Many of us suffer from unrefreshing sleep so my thought was this system could be impaired by this too.

Then there is the big question, if it is mitochondrial dysfunction why are other tissues/organs not affected? I think the answer here lies in the different affinities in the CNS of SSRI's/Finasteride. Here trazodone led to oxidative stress in the testicles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087606/

Many of us suffer from chronic fatigue and muscle weakness, I used to be a regular gym visitor and as supplement I used creatine, before PSSD I never noticed direct benefits from it, last year with PSSD I noticed I felt significantly stronger in the gym from creatine. My thought was the creatine increased the ATP (at least systemic) and led to improvements of cell function.

Edit: Also some here got improvements from HBOT (Hyperbaric Oxygen), which leads to decreased mitochondrial oxidative stress after repeated use, from what I know.

In addition to this, we might suffer from LTP impairment in the hippocampus: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214920/

And the good old 5HT1A autoreceptor desensitization.

My theory is those suffering only from sexual symptoms only get the faulty neurotransmission from 5HT1A autoreceptor desensitization, while those severe get the full package of mitochondrial disruption and LTP impairment in the hippocampus. This is all down stream of epigenetic changes.

Let's discuss why this could/could not have happened.
Hi mate.. What parts of PSSD do you suffer from? And also which symptoms does creatine help you with?
Last edited by JP1985 on Wed Aug 12, 2020 6:03 pm, edited 1 time in total.
Last pill March 2019 - Citalopram for 7 years
Numbed penis and weak orgasm
Fatigue
Slightly blunted
Dizziness (this has improved a lot in the last 6 months)
PsychoGenesis
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Re: PSSD as mitochondrial disorder

Unread post by PsychoGenesis »

following
cdraham
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Re: PSSD as mitochondrial disorder

Unread post by cdraham »

JP1985 wrote: Wed Aug 12, 2020 4:49 pm
cdraham wrote: Wed Aug 12, 2020 10:08 am Hello,

I have severe PSSD for more than 1.5 years and after doing alot of reading I think at the core of PSSD there is mitochondrial dysfunction. I've been in contact with neuroscientists, etc. over twitter and weve been exchanging ideas how this could have happened.

SSRI's have been found to disrupt mitochondrial function:

https://pubmed.ncbi.nlm.nih.gov/18344530/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777788/

"In human hepatocytes that express cytochrome P450, isoform 3A4, after 24 h exposure, nefazodone and trazodone collapsed mitochondrial membrane potential, and imposed oxidative stress, as detected via glutathione depletion, leading to cell death. "

When this mitochondrial dysfunction happens, oxidative/inflammatory cascades could lead to epigenetic changes of the androgen receptor:

https://www.sciencedirect.com/science/a ... 5618300139

"ATZ caused transcriptional repression of the spermatogenesis-related genes SRD5A2 and CFTR, the antioxidant defense genes SOD2 and GPX4B, and the DNA repair gene XPC"

(ATZ is not SSRIS but disrupted the same mitochondrial membranes as SSRIs did)

Crosstalk between mitochondria and androgens:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922316/

We know in Post Finasteride Syndrome SRD5A2 is methylated:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652249/

Now what happens when the mitochondria is dysfunctional? Not enough ATP is produced. ATP is the energy source of cells and it is required for receptors to function. It is involved in many functions of the body. For example the glymphatic system, the waste detox system of the brain, is highly dependent on ATP. Many of us suffer from unrefreshing sleep so my thought was this system could be impaired by this too.

Then there is the big question, if it is mitochondrial dysfunction why are other tissues/organs not affected? I think the answer here lies in the different affinities in the CNS of SSRI's/Finasteride. Here trazodone led to oxidative stress in the testicles: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087606/

Many of us suffer from chronic fatigue and muscle weakness, I used to be a regular gym visitor and as supplement I used creatine, before PSSD I never noticed direct benefits from it, last year with PSSD I noticed I felt significantly stronger in the gym from creatine. My thought was the creatine increased the ATP (at least systemic) and led to improvements of cell function.

Edit: Also some here got improvements from HBOT (Hyperbaric Oxygen), which leads to decreased mitochondrial oxidative stress after repeated use, from what I know.

In addition to this, we might suffer from LTP impairment in the hippocampus: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214920/

And the good old 5HT1A autoreceptor desensitization.

My theory is those suffering only from sexual symptoms only get the faulty neurotransmission from 5HT1A autoreceptor desensitization, while those severe get the full package of mitochondrial disruption and LTP impairment in the hippocampus. This is all down stream of epigenetic changes.

Let's discuss why this could/could not have happened.
Hi mate.. What parts of PSSD do you suffer from? And also which symptoms does creatine help you with?
I have every symptom in the book. Creatine helped with strength in gym.
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kpavel
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Re: PSSD as mitochondrial disorder

Unread post by kpavel »

HereToHeal wrote: Wed Aug 12, 2020 11:10 am Kpavel had a similar theory. He took a stack of supplements and seemed to have getting good results.
You should get him involved in your research.
Yeah, right, only I payed more attention to cardiovascular symptoms. I pay attention to memory issues too now. And I didn't use creatine or that type of probiotic, so the stack isn't complete. There will be other clues and connections.
Thomas
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Re: PSSD could be a mitochondrial disorder

Unread post by Thomas »

How would your theories explain the timeframe of the symptoms? Lots of sufferers (including myself) had worsening symptoms after quitting. The only explaination I found so far is psychological but it doesn't feel right for me (I became worried when symptoms worsened, not the opposite)
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: PSSD could be a mitochondrial disorder

Unread post by cdraham »

Thomas wrote: Thu Aug 13, 2020 6:49 pm How would your theories explain the timeframe of the symptoms? Lots of sufferers (including myself) had worsening symptoms after quitting. The only explaination I found so far is psychological but it doesn't feel right for me (I became worried when symptoms worsened, not the opposite)
Thomas wrote: Thu Aug 13, 2020 6:49 pm How would your theories explain the timeframe of the symptoms? Lots of sufferers (including myself) had worsening symptoms after quitting. The only explaination I found so far is psychological but it doesn't feel right for me (I became worried when symptoms worsened, not the opposite)
It was shown that often the most epigenetic changes happen in drug withdrawal, this is not just with SSRIs but theres the citalopram study where literally hundreds of genes were changed upon withdrawal.
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succubus76
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Re: PSSD could be a mitochondrial disorder

Unread post by succubus76 »

cdraham wrote: Wed Aug 12, 2020 10:08 am

And the good old 5HT1A autoreceptor desensitization.

Did meso disproved this whit the vortioxetine trial? Lol
I dont think it holds true
cdraham
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Re: PSSD could be a mitochondrial disorder

Unread post by cdraham »

succubus76 wrote: Fri Aug 14, 2020 2:14 am
cdraham wrote: Wed Aug 12, 2020 10:08 am

And the good old 5HT1A autoreceptor desensitization.

Did meso disproved this whit the vortioxetine trial? Lol
I dont think it holds true
I don't think he proved anything. Can you send me a link?
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