Potential Avenues to Investigate

This is for hypothesis and even educated speculation.
naiverat
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Potential Avenues to Investigate

Unread post by naiverat »

I recently spoke with someone highly knowledgeable in the realm of biochemistry, and they suggested that a reduced metabolic rate may underpin PSSD's classic symptoms. What are your opinions regarding this theory? If you have thyroid numbers, please post them here. Also, let's start taking our body temps and comparing them!

Their words:

"PSSD specifically isn't something I'm an expert on, though I do have a strong knowledge base on serotonin in general, which may offer some insight.

My first port of call would be to investigate allopregnanolone if you haven't yet done so. Allopreg is the most potent endogenous GABA-A agonist, and SSRI's directly alter the activity of brain 3a-hydroxysteroid dehydrogenase -- the enzyme which produces it.

Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes.

https://www.pnas.org/content/96/23/13512

SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670606/

Altered levels of allopregnanolone are purported to be directly causative in the development of depression and anxiety due to the loss of GABAergic tone. A lot of the symptoms of PSSD are well aligned with the symptoms of low GABA.

The Role of Allopregnanolone in Depression and Anxiety.

https://pubmed.ncbi.nlm.nih.gov/2421579 ... aggression.

If you find this theory fits your situation, you could consider the use of pregnenolone, progesterone and/or 5a-dihydroprogesterone to see if you can start moving things in the right direction. You mentioned neurosteroids a lot in your message, so you may have already tried the above. Regardless, the former are two are safe to take indefinitely, and are much, much safer than testosterone, so I would still consider their use throughout the recovery process.

Allopregnanolone Elevations Following Pregnenolone Administration are Associated with Enhanced Activation of Emotion Regulation Neurocircuits.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648625/

Regarding testosterone: I won't directly instruct you on what to do, but if I were in your situation, I would definitely use it as a last resort. The shutdown of the HPTA and subsequent suppression of upstream hormone production isn't something that is remedied by hcg, in my opinion. HCG is not LH, and evokes an entirely different response at the LH receptor compared to LH itself. If HCG and LH were the same, the pregnant women from whom it was extracted from would have just produced more LH -- HCG has it's own unique biological effects, and in my opinion, it is not the benign LH analogue it is made out to be.

Anecdotally, TRT gave me a lot of the very symptoms you described -- strong anhedonia and CNS issues, but also impaired cognition, anxiety and depressive tendencies. I used HCG throughout my entire time on testosterone too, yet my progesterone (the precursor to allopreg) was always undetectable. It also did nothing to improve my erection quality or libido. I've been off for over a year now, and have since recovered from the aforementioned side effects through the use of dhea, progesterone and thyroid, which might also be applicable to you. Here is a comment I recently made to someone else, which will help give you some much needed context:

The 5-HT deficiency model of depression is now largely rejected. A lot of the recent data is now suggesting the opposite: brain serotonin is seen elevated in those with depression, and is purported to play a causative role in it's development. This recent review provides an incredibly comprehensive overview of the topic, and offers a great base for the desperately needed paradigm shift in the view of depression:

Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response:

https://www.sciencedirect.com/science/a ... 3415000287

The only reason the theory has remained relevant despite the accumulation of data to the contrary is that SSRI's do seem to improve depressive symptoms in a small minority. However, a semi-recent study in mice with genetically-induced tryptophan hydroxylase 2 deficiency did not display depressive behavior. Furthermore, when placed under extreme stress, a small proportion of those same mice demonstrated beneficial effects from the administration of an SSRI.

Mice Genetically Depleted of Brain Serotonin do not Display a Depression-like Behavioral Phenotype:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777283/

This is largely a product of the aforementioned increase in allopregnanolone production, but there is also data suggesting altered circadian rhythm, altered cortisol metabolism and various other neuroendocrine influences, again supporting the suggestion that the effectiveness of SSRI's is not an indicator that the underlying pathology is deficient serotonin:

Neuroimmune endocrine effects of antidepressants:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280108/

As touched upon in the aforementioned "upper or downer" review, serotonin acts to directly downregulate the metabolic rate of the cell during times of stress. Cortisol, the primary glucocorticoid mediator of long-term stress in the body, directly increases the expression of the aromatase enzyme, which in turn increases systemic estrogen production, and thus the levels of brain 5-HT. There is a commonality between all these hormones: they work together to decrease the systemic metabolic rate during times of stress. This serves as a compensatory mechanism to conserve energy, all to confer a survival benefit to the organism until said stressor is overcome. Herein lies the problem in depression: the chronic elevation of serotonin is the product of a maladaption to a chronic stressor, which leads to the indefinite suppression of the endogenous energy producing systems, and thus the metabolic rate. Although the ability to downregulate the metabolic rate is extremely important for short term survival, being trapped in this stress-induced low energy state for an extended period leads to a systemic energetic deficiency; tissues are poorly repaired, cells become unable to adequately fulfill their differentiated role, and the overall efficiency of the body starts to slowly decline as unopposed catabolism ensues. Structure and function are interdependent at every level; as soon as the energy which underlies the function declines, so does the structure. This is the problem with modern medicine -- we treat man like dead matter, with no regard for the bioenergetics which underlies all cellular processes.

The hallmark of impaired energy production, and by-proxy the metabolic rate, is a shift away from the oxidation of glucose, towards a metabolism predominated by glycolysis in glucose-dependent tissue (the brain), and beta oxidation of fatty acids in the periphery. This is the exact state that serotonin is 'designed' (for lack of a better phrase) to produce, and is exactly what is seen in those with depression:

The Energy Metabolism Dysfunction in Psychiatric Disorders Postmortem Brains: Focus on Proteomic Evidence:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594406/

Mitochondrial Dysfunction in Depression:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981740/

Brain Glucose Metabolism in an Animal Model of Depression:

https://pubmed.ncbi.nlm.nih.gov/25819664/

When you view depression from a metabolic standpoint, it becomes clear as to why elevated serotonin is not conducive to good mental health, why it's deficiency is not the cause of depression, and why SSRI's are not an effective or desired treatment.

Why is this applicable to you?

Because all of your symptoms are suggestive of an impaired metabolic rate, which may have been caused by the SSRI- induced chronic elevation of systemic circulating serotonin. The conversion of cholesterol -> pregnenolone, and thus the production of all protective downstream steroids/neurosteroids, is a thyroid-dependent process which occurs inside the mitochondria. Thyroid hormone, specifically the active T3, acts to drive the oxidative phosphorylation of glucose, producing large amounts of ATP, and effectively 'energizing' the cell. The inhibition of T3-dependent glucose oxidation is the main mechanism by which the aforementioned hormones of stress directly downregulate the metabolic rate, the byproduct of this being impaired cholesterol -> pregnenolone conversion, and thus lowered downstream steroid/neurosteroid production. Again, these hormones of stress are elevated as a compensatory mechanism to conserve energy; a time when energetically demanding hormones like testosterone, progesterone and thyroid which produce large-scale anabolism cannot be facilitated -- hence the downregulation of their production.

Cholesterol -> Pregnenolone conversion: https://i.imgur.com/DjnXNIV.png

The problem here is that SSRI-induced elevations in serotonin signal systemic metabolic downregulation, even when the usual stressors that induce said state are not present. As I mentioned prior, all of your symptoms are indicative of low energy production.

The best measure of the metabolic rate is the body temperature. The metabolic rate is merely the refection, or summation, of the rate of every single reaction in your body. Those reactions all produce heat as a byproduct, so if your body temperature is low, it is an indicator that the metabolic rate is, too. An optimal body temperature is 36.5c upon waking, rising to 37c by mid-afternoon. Buy a cheap digital thermometer, place it under your arm for three minutes until it's adjusted to your temps, and write down your result. Do this upon waking and an hour post breakfast for a week. This will give you a good idea where you currently stand.

As I mentioned previously, thyroid hormone is the main determinant of the metabolic rate. This makes thyroid blood work useful. However, thyroid hormone is not like the steroid hormones, in that the levels in the blood is not a good indicator of systemic thyroid activity, or the metabolic rate in general. This is because there are various factors that can directly block the ability of thyroid hormone to exert it's action in the cell, independent of changes to the actual output from the gland, and therefore serum levels. TSH, fT3, fT4, TT4, TT3, rT3, cortisol and cholesterol are all great indicators of thyroid function, and thus the metabolic rate."
Fluoxetine Jan. '16 - Aug. 16'. Low libido, weak erections, CNS dysfunction, anhedonia

Windows on the following: Inositol, choline, NAC + Histidine, MSM, SJW, L-Arginine, Sildenafil, Naltrexone, boron
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kpavel
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Re: Potential Avenues to Investigate

Unread post by kpavel »

So basically the stuff is really interesting. My only doubt is how really allo feels sexually. And I knew ht2b receptors in astrocytes etc do something with gluconeogenesis or such. Is there any specific set of proteins that switch off oxidative phosphorylation to glucose use? SSRI phosphorylate GSK beta.
Also looked briefly, it could be that rexinoid receptor alpha and vdr control steroidogenesis. And RXR receptors infuence thyroid hormone.
https://pubmed.ncbi.nlm.nih.gov/19744992/
https://pubmed.ncbi.nlm.nih.gov/22761456/
https://pubmed.ncbi.nlm.nih.gov/11803135/
Anyway, that could be something to dig a little deeper.
Oleya
Posts: 14
Joined: Tue Apr 28, 2020 6:27 am

Re: Potential Avenues to Investigate

Unread post by Oleya »

naiverat wrote: Tue Jul 07, 2020 11:39 pm I recently spoke with someone highly knowledgeable in the realm of biochemistry, and they suggested that a reduced metabolic rate may underpin PSSD's classic symptoms. What are your opinions regarding this theory? If you have thyroid numbers, please post them here. Also, let's start taking our body temps and comparing them!

Their words:

"PSSD specifically isn't something I'm an expert on, though I do have a strong knowledge base on serotonin in general, which may offer some insight.

My first port of call would be to investigate allopregnanolone if you haven't yet done so. Allopreg is the most potent endogenous GABA-A agonist, and SSRI's directly alter the activity of brain 3a-hydroxysteroid dehydrogenase -- the enzyme which produces it.

Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes.

https://www.pnas.org/content/96/23/13512

SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670606/

Altered levels of allopregnanolone are purported to be directly causative in the development of depression and anxiety due to the loss of GABAergic tone. A lot of the symptoms of PSSD are well aligned with the symptoms of low GABA.

The Role of Allopregnanolone in Depression and Anxiety.

https://pubmed.ncbi.nlm.nih.gov/2421579 ... aggression.

If you find this theory fits your situation, you could consider the use of pregnenolone, progesterone and/or 5a-dihydroprogesterone to see if you can start moving things in the right direction. You mentioned neurosteroids a lot in your message, so you may have already tried the above. Regardless, the former are two are safe to take indefinitely, and are much, much safer than testosterone, so I would still consider their use throughout the recovery process.

Allopregnanolone Elevations Following Pregnenolone Administration are Associated with Enhanced Activation of Emotion Regulation Neurocircuits.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648625/

Regarding testosterone: I won't directly instruct you on what to do, but if I were in your situation, I would definitely use it as a last resort. The shutdown of the HPTA and subsequent suppression of upstream hormone production isn't something that is remedied by hcg, in my opinion. HCG is not LH, and evokes an entirely different response at the LH receptor compared to LH itself. If HCG and LH were the same, the pregnant women from whom it was extracted from would have just produced more LH -- HCG has it's own unique biological effects, and in my opinion, it is not the benign LH analogue it is made out to be.

Anecdotally, TRT gave me a lot of the very symptoms you described -- strong anhedonia and CNS issues, but also impaired cognition, anxiety and depressive tendencies. I used HCG throughout my entire time on testosterone too, yet my progesterone (the precursor to allopreg) was always undetectable. It also did nothing to improve my erection quality or libido. I've been off for over a year now, and have since recovered from the aforementioned side effects through the use of dhea, progesterone and thyroid, which might also be applicable to you. Here is a comment I recently made to someone else, which will help give you some much needed context:

The 5-HT deficiency model of depression is now largely rejected. A lot of the recent data is now suggesting the opposite: brain serotonin is seen elevated in those with depression, and is purported to play a causative role in it's development. This recent review provides an incredibly comprehensive overview of the topic, and offers a great base for the desperately needed paradigm shift in the view of depression:

Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response:

https://www.sciencedirect.com/science/a ... 3415000287

The only reason the theory has remained relevant despite the accumulation of data to the contrary is that SSRI's do seem to improve depressive symptoms in a small minority. However, a semi-recent study in mice with genetically-induced tryptophan hydroxylase 2 deficiency did not display depressive behavior. Furthermore, when placed under extreme stress, a small proportion of those same mice demonstrated beneficial effects from the administration of an SSRI.

Mice Genetically Depleted of Brain Serotonin do not Display a Depression-like Behavioral Phenotype:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777283/

This is largely a product of the aforementioned increase in allopregnanolone production, but there is also data suggesting altered circadian rhythm, altered cortisol metabolism and various other neuroendocrine influences, again supporting the suggestion that the effectiveness of SSRI's is not an indicator that the underlying pathology is deficient serotonin:

Neuroimmune endocrine effects of antidepressants:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280108/

As touched upon in the aforementioned "upper or downer" review, serotonin acts to directly downregulate the metabolic rate of the cell during times of stress. Cortisol, the primary glucocorticoid mediator of long-term stress in the body, directly increases the expression of the aromatase enzyme, which in turn increases systemic estrogen production, and thus the levels of brain 5-HT. There is a commonality between all these hormones: they work together to decrease the systemic metabolic rate during times of stress. This serves as a compensatory mechanism to conserve energy, all to confer a survival benefit to the organism until said stressor is overcome. Herein lies the problem in depression: the chronic elevation of serotonin is the product of a maladaption to a chronic stressor, which leads to the indefinite suppression of the endogenous energy producing systems, and thus the metabolic rate. Although the ability to downregulate the metabolic rate is extremely important for short term survival, being trapped in this stress-induced low energy state for an extended period leads to a systemic energetic deficiency; tissues are poorly repaired, cells become unable to adequately fulfill their differentiated role, and the overall efficiency of the body starts to slowly decline as unopposed catabolism ensues. Structure and function are interdependent at every level; as soon as the energy which underlies the function declines, so does the structure. This is the problem with modern medicine -- we treat man like dead matter, with no regard for the bioenergetics which underlies all cellular processes.

The hallmark of impaired energy production, and by-proxy the metabolic rate, is a shift away from the oxidation of glucose, towards a metabolism predominated by glycolysis in glucose-dependent tissue (the brain), and beta oxidation of fatty acids in the periphery. This is the exact state that serotonin is 'designed' (for lack of a better phrase) to produce, and is exactly what is seen in those with depression:

The Energy Metabolism Dysfunction in Psychiatric Disorders Postmortem Brains: Focus on Proteomic Evidence:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5594406/

Mitochondrial Dysfunction in Depression:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981740/

Brain Glucose Metabolism in an Animal Model of Depression:

https://pubmed.ncbi.nlm.nih.gov/25819664/

When you view depression from a metabolic standpoint, it becomes clear as to why elevated serotonin is not conducive to good mental health, why it's deficiency is not the cause of depression, and why SSRI's are not an effective or desired treatment.

Why is this applicable to you?

Because all of your symptoms are suggestive of an impaired metabolic rate, which may have been caused by the SSRI- induced chronic elevation of systemic circulating serotonin. The conversion of cholesterol -> pregnenolone, and thus the production of all protective downstream steroids/neurosteroids, is a thyroid-dependent process which occurs inside the mitochondria. Thyroid hormone, specifically the active T3, acts to drive the oxidative phosphorylation of glucose, producing large amounts of ATP, and effectively 'energizing' the cell. The inhibition of T3-dependent glucose oxidation is the main mechanism by which the aforementioned hormones of stress directly downregulate the metabolic rate, the byproduct of this being impaired cholesterol -> pregnenolone conversion, and thus lowered downstream steroid/neurosteroid production. Again, these hormones of stress are elevated as a compensatory mechanism to conserve energy; a time when energetically demanding hormones like testosterone, progesterone and thyroid which produce large-scale anabolism cannot be facilitated -- hence the downregulation of their production.

Cholesterol -> Pregnenolone conversion: https://i.imgur.com/DjnXNIV.png

The problem here is that SSRI-induced elevations in serotonin signal systemic metabolic downregulation, even when the usual stressors that induce said state are not present. As I mentioned prior, all of your symptoms are indicative of low energy production.

The best measure of the metabolic rate is the body temperature. The metabolic rate is merely the refection, or summation, of the rate of every single reaction in your body. Those reactions all produce heat as a byproduct, so if your body temperature is low, it is an indicator that the metabolic rate is, too. An optimal body temperature is 36.5c upon waking, rising to 37c by mid-afternoon. Buy a cheap digital thermometer, place it under your arm for three minutes until it's adjusted to your temps, and write down your result. Do this upon waking and an hour post breakfast for a week. This will give you a good idea where you currently stand.

As I mentioned previously, thyroid hormone is the main determinant of the metabolic rate. This makes thyroid blood work useful. However, thyroid hormone is not like the steroid hormones, in that the levels in the blood is not a good indicator of systemic thyroid activity, or the metabolic rate in general. This is because there are various factors that can directly block the ability of thyroid hormone to exert it's action in the cell, independent of changes to the actual output from the gland, and therefore serum levels. TSH, fT3, fT4, TT4, TT3, rT3, cortisol and cholesterol are all great indicators of thyroid function, and thus the metabolic rate."
This could be the point. I was diagnosed with severe hashimoto hypothyroidism after using ssri. Despite the presence of thyroid hormone (both T3 and T4) my temperatures are always low (35.4 °), despite my Tsh being in the range. What can be done to raise temperatures? In my opinion this is an important point. Help me!
cdraham
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Re: Potential Avenues to Investigate

Unread post by cdraham »

Maybe try 5a DHP? Im considering to order it from sigma aldrich
defmyst
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Re: Potential Avenues to Investigate

Unread post by defmyst »

I am skeptical at this theory. The symptoms/condition described is very general in nature. In my opinion, if this was the sole cause for everyone experiencing PSSD I think it would have been detected by now. I think the problem is much more nuanced in nature.
naiverat
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Re: Potential Avenues to Investigate

Unread post by naiverat »

It may not be the cause, but it could contribute to symptoms potentially. Many people with PSSD show borderline low T levels and have fatigue. It would be interesting to have more thyroid numbers (not just TSH, which itself has a huge range and isn't usually optimized by physicians).

Since developing PSSD, I have significant issues with stimuli causing CNS overstimulation. Perhaps inhibitory steroids, or lack thereof, -- the main one being allopreg -- could be responsible for this.

I've only measured preg and DHEA-S once on a blood test, and *both* of the numbers were outside of the normal range. I'm not sure if that's just because I'm young and these tests are typically run on older people, or the numbers were actually legitimately high for my age. If the latter, why? Are they not converting properly to the downstream neurosteroids due to a lack of catalyzing enzymes? I'm sure there are tests for the other neurosteroids, but who knows the accuracy and I'm sure they're extremely expensive.

I'll try running 25 mg DHEA + 25 mg preg for a couple weeks and report back.
Fluoxetine Jan. '16 - Aug. 16'. Low libido, weak erections, CNS dysfunction, anhedonia

Windows on the following: Inositol, choline, NAC + Histidine, MSM, SJW, L-Arginine, Sildenafil, Naltrexone, boron
naiverat
Posts: 253
Joined: Mon Dec 18, 2017 4:41 pm
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Re: Potential Avenues to Investigate

Unread post by naiverat »

kpavel wrote: Wed Jul 08, 2020 4:09 am So basically the stuff is really interesting. My only doubt is how really allo feels sexually. And I knew ht2b receptors in astrocytes etc do something with gluconeogenesis or such. Is there any specific set of proteins that switch off oxidative phosphorylation to glucose use? SSRI phosphorylate GSK beta.
Also looked briefly, it could be that rexinoid receptor alpha and vdr control steroidogenesis. And RXR receptors infuence thyroid hormone.
https://pubmed.ncbi.nlm.nih.gov/19744992/
https://pubmed.ncbi.nlm.nih.gov/22761456/
https://pubmed.ncbi.nlm.nih.gov/11803135/
Anyway, that could be something to dig a little deeper.
Yes - it seems allopreg is really emphasized in the post-drug communities, especially by the PFS folks. I can see lack of inhibitory neurosteroids potentially causing the sleep and anxiety issues commonly seen with fin, but I'm doubtful that the the majority of sexual issues are caused by a deficiency of allo.
Fluoxetine Jan. '16 - Aug. 16'. Low libido, weak erections, CNS dysfunction, anhedonia

Windows on the following: Inositol, choline, NAC + Histidine, MSM, SJW, L-Arginine, Sildenafil, Naltrexone, boron
Maxin
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Re: Potential Avenues to Investigate

Unread post by Maxin »

It’s true that temp is down for a lot of us with pssd and the thyroid isn’t functioning properly. But many of us have tried various forms of thyroid to no avail. My tsh is high but I feel 10 times worse on any thyroid forms. Cortisol is not functioning properly and for many of us causes a worse crash. If only it was this simple pssd would be a thing of the past. It’s not unfortunately. Most of us have tried pregnenelone as well.
malink
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Re: Potential Avenues to Investigate

Unread post by malink »

I find this theory correct! I am in a situation of a reduced metabolic rate. I was diagnosed with Hashimoto's disease and despite the addition of thyroid medications (increasing more and more with no results, I also added T3), my basal temperature is always low, my metabolism is slow (I gain a lot) and I lose a lot of hair. I have tried supplementing with Preg, but to no avail. What could I do in your opinion?
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Delfador
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Re: Potential Avenues to Investigate

Unread post by Delfador »

My metabolism is EXTREMELY high. Possibly one of the highest in the world. I eat healthilly and only weight 49 kilograms at 6ft2.

However, that also means im on gluconeogenesis all the time so your theory might have some truth to it.

My thyroid numbers are in normal range. They have always bern normal.
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